Covalent small molecule DCN1 inhibitors and therapeutic methods using the same

ABSTRACT

Small molecule covalent inhibitors of DCN1 and compositions containing the same are disclosed. Methods of using the DCN1 covalent inhibitors in the treatment of diseases and conditions wherein inhibition of DCN1 provides a benefit, like oxidative stress-related diseases and conditions, neurodegenerative diseases and conditions, metabolic disorders, and muscular nerve degeneration, also are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional PatentApplication No. 62/483,640 filed Apr. 10, 2017, incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to small molecule DCN1 inhibitors whichbind covalently to the protein, and to therapeutic methods of treatingconditions and diseases wherein inhibition of DCN1 provides a benefit.

BACKGROUND OF THE INVENTION

The regulated destruction of intracellular proteins is controlled by theubiquitin-proteasome system (UPS) via tagging the ubiquitin on theproteins, and is essential to cellular protein homeostasis (1,2). TheUPS has been extensively pursued as a drug target (3,4), with twoproteasome inhibitors, Bortezomib and Carfilzomib, having been approvedfor the treatment of multiple myeloma (5-7).

The Cullin-Ring ligases (CRL), a central component of the UPS, regulatethe turnover of approximately 20% of cellular proteins, and thedysregulation of CRLs plays a critical role in various human diseases,including cancer, cardiovascular diseases, neurodegenerative disorders,and viral infections (8-11). The activation of CRLs is controlled byNEDD8 (neural precursor cell expressed developmentally downregulatedprotein 8), a ubiquitin-like protein (9,10,12). Analogous to the processof ubiquitination, neddylation is a process by which the ubiquitin-likeprotein NEDD8 is conjugated to its target proteins.

The neddylation cascade begins with the activation of NEDD8 by an E1enzyme, the NEDD8 activating enzyme (NAE), followed by transfer of theactivated NEDD8 to one of two NEDD8-specific E2 enzymes, UBC12 andUBE2F. In the final step of this cascade, an E3 enzyme catalyzes thetransfer of NEDD8 from E2 to target substrates (13). The enzymes of theNEDD8 pathway have been pursued as potential therapeutic targets (14-17)and MLN4924, an inhibitor of the E1 enzyme NAE, was shown to suppresstumor cell growth both in vitro and in vivo (18). Mechanistically,MLN4924 inhibits NAE enzymatic activity through formation of a covalentNEDD8-MLN4924 adduct, which in turn inactivates CRLs, leading toaccumulation of CRL substrates (18,19). MLN4924 is currently beingtested in clinical trials for the treatment of human cancers (20).

Schulman et al. have defined both the structural and biochemicalmechanisms underlying the E1-E2-E3 cascade reaction in the NEDD8 pathway(13, 21-23). Schulman et al. further demonstrated that DCN1, ascaffold-like E3 ligase, facilitates the transfer of NEDD8 from UBC12 tocullins through its interaction with UBC12 and enhances the enzymaticactivity of cullins (13,22,23). The co-crystal structure of theDCN1-UBC12 complex 22,23 reveals that UBC12 interacts with DCN1 throughtwo distinct sites and the N-terminally acetylated UBC12 peptide bindsto a well-defined pocket in DCN1.

To date, no small-molecule inhibitors of the DCN1-UBC12 interaction havebeen advanced into clinical development. Accordingly, a need stillexists in the art for small molecule inhibitors of the UBC12-DCN1protein-protein interaction, having physical and pharmacologicalproperties that permit use of such inhibitors in a range of therapeuticapplications in which modulation of the activity of cullins may have atherapeutic benefit.

Inhibitors of protein-protein interactions are generally considered tobe difficult drugs to develop, because even when there is a well definedbinding pocket on one of the proteins to target, that is rarely thetotality of the mutual binding surface between the two entities. Wheninhibiting receptors or enzymes, there is often a small molecule ligandor cofactor which can be competed against, or a catalytic machinerywhich can be interfered with irrespective of substrate binding, and thisallows relatively low affinity inhibitors to be potential drugs.However, with protein-protein interaction inhibitors (PPI inhibitors) itis frequently infeasible to block the whole of the interaction sitebetween the two proteins, and if one is only blocking a part of theinteraction site, very high affinity ligands are required in order tocompete with the partner protein which will interact with a much largerprotein surface than the inhibitor. Even with very good binding pockets,it is difficult to push binding affinities into the frequently requiredlow picomolar range.

One answer to achieve highly potent inhibition of the protein-proteininteraction is to use an inhibitor which forms a covalent bond to itstarget protein, as bond formation makes the effective binding betweeninhibitor and target protein much stronger. In recent years, thisapproach has been systematized, especially in the kinase inhibitorfield, where a combination of intrinsically high affinity ligands,combined with a very precisely placed weak electrophile, usually closeto a highly nucleophilic cysteine residue, has been shown to produceinhibitors which bind very strongly indeed to the target protein, butwhich are of intrinsically low enough chemical reactivity to have usablepharmacokinetics and acceptable off target toxicity profiles. Forexamples Afatinib, Ibrutinib and Osimertinib are all successfulanticancer drugs which covalently attach to a cysteine on the edge ofthe ATP-binding domain in a small subset of kinases.

DCN1 has a cysteine (Cys¹¹⁵) on the edge of its deep UBC12 bindingpocket, and in a suitable place whereby DCN1 inhibitors of the chemotypedescribed in a previous patent application [U.S. Provisional ApplicationNo. 62/477,498], and illustrated herewithin, should be able to present asuitable electrophile in a manner to allow formation of a covalent bondbetween the cysteine sulfur atom and the abovementioned electrophile.Compounds of the present invention can bind to DCN1 as covalentinhibitors of the interaction between DCN1 and UBC12, and this leads toa major, highly consequential boost in their potency for these moleculesas compared to their non-covalent inhibitor counterparts.

SUMMARY OF THE INVENTION

The present invention is directed to small-molecule inhibitors designedto bind to the UBC12 binding site in DCN1 (hereafter called DCN1inhibitors), and to form a covalent bond between their electrophilicmoiety and Cys¹¹⁵ of DCN1, to compositions comprising the inhibitors,and to methods of using the inhibitors in a therapeutic treatment ofconditions and diseases wherein inhibition of the UBC12 binding site inDCN1 provides a benefit. In particularly, the present compounds arepotent inhibitors of the DCN1-UBC12 protein-protein interaction. Theinhibitors block neddylation of cullin 3. The inhibitors also blockneddylation of other cullins, although at higher concentrations thanthose used for inhibition of the neddylation of cullin 3.

More particularly, the present invention is directed to compounds havinga structural formula (I),

wherein;

Q is C═O, C═S or SO₂;

Ar₁ is a five or six-membered aromatic or heteroaromatic ring or abicyclic aromatic or heteroaromatic ring having 8-12 atoms, including upto four heteroatoms chosen from N, O and S, in a chemically stablearrangement, optionally substituted with up to four R₂ substitutents;

X is selected from a bond, CR₇R₈, CR₇R₈NR₁₂, CR₇R₈NR₁₂CO,CR₇R₈NR₁₂CONR₁₂, CR₇R₈NR₁₂SO₂, CR₇R₈O, CR₇R₈S(O)x CONR₁₂;

Y is selected from C₁₋₆ alkylidyl, C₃₋₆ cycloalkylidyl, C₄₋₇heterocloalkylidyl, arylene, heteroarylene, aryl(m)ethylene,heteroaryl(m)ethylene, fused C₅₋₈ bicycloalkylidyl or C₅₋₉spirocycloalkylidyl;

Or Y and R₉ are taken together with the nitrogen atom to which they areattached to form a heterocyclic or heteroaryl ring of four to sevenmembers, optionally including any chemically stable combination of oneto three groups selected from O, C═O, N, NR₅ and S;

Z is

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl;

R₂ are independently selected from the group consisting of halo, CN, N₃,CF₃, NO₂, H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₂₋₆ alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆cycloalkyl, substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substitutedC₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, phenyl, substituted phenyl,monocyclic heteroaryl, substituted monocyclic heteroaryl, OR₅, NR₃R₄,COOR₅, CONR₃R₄;

R₃ and R₄, independently, are selected from the group consisting ofhydrogen, C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl,heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₁₋₆ alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, or are taken together with the nitrogen atom towhich they are attached to form a ring of four to seven members,optionally including any chemically stable combination of one to threeO, C═O, NR₅ and S;

R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂, C₁₋₆alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl,C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, each optionally substituted with up to threesubstituents independently selected from halo, hydroxy, oxo, thio,thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₄₋₇ heterocycloalkyl, aryl, and heteroaryl;

R₆ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, C₂₋₆ alkynyl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl. C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆ alkylaryl, heteroaryl, C₁₋₆alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl and C₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl;

R₇ and R₈ may be independently H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl,C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl, C₂₋₆ alkynyl, substituted C₂₋₆alkynyl, or taken together with the C atom to which they are attached,form a carbonyl group, a thionyl group, an oxime, a hydrazone, C₃₋₆cycloalkyl, substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substitutedC₄₋₆ cycloalkenyl or C₄₋₇ heterocycloalkyl:

R₉ is selected from the group consisting of H, C₁₋₆ alkyl, substitutedC₁₋₆ alkyl, C₃₋₆ alkenyl, substituted C₃₋₆ alkenyl, C₃₋₆ alkynyl,substituted C₃₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, phenyl, substitutedphenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl or C₄₋₇heterocycloalkyl:

R₁₀ is H, F, Cl, CF₃, CHF₂, (CH₂)_(n)NR₃R₄, CH₂SO₂R₁₂, CH₂OCOR₁₂, CN orR₁₂;

R_(11e) is H, R₁₂, (CH₂)_(n)R₂, CF₂(CH₂)xR₂, COR₅, CO₂R₅ or CONR₃R₄;

R_(11z) is H, F, Cl, CF₃, CHF₂, CF₂R₁₂ or R₁₂;

Or R_(11e) and R_(11z) may be taken together with the sp² carbon atom towhich both are bonded to form an alicyclic ring of 4 to 7 members whereone of the ring atoms may be NR₁₂, O, or S(O)_(x), optionallysubstituted with halogen, oxo, OH, OR₅, NR₃R₄;

Or R_(11e) and R_(11z) taken together may be R_(11e)R_(11z)C═, formingan allenyl group;

Or R₁₀ and R_(11e) may be taken together with the sp² C atoms to whichthey are attached to form a partially saturated carbocyclic orheterocyclic ring of 5-7 atoms, with up to two of the ring atoms beingO, S(O)_(x), NR₁₂, and said ring may be substituted with hydroxy, oxo,C₁₋₆ alkoxy,

R_(11t) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl, C₄₋₇heterocycloalkyl, CH₂NR₃R₄;

R₁₂ is H or C₁₋₆ alkyl, either straight chain or branched;

T is halogen, SS—C₁₋₆ lower alkyl, pentafluorophenoxy,tetrafluorophenoxy:

n is 1, 2 or 3;

x is 0, 1, or 2;

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In one embodiment, the present invention provides a method of treating acondition or disease by administering a therapeutically effective amountof a compound of structural formula (I) to an individual in needthereof. The disease or condition of interest is treatable by inhibitionof DCN1, for example, an oxidative stress-related disease or aneurodegenerative disease.

Another embodiment of the present invention is to provide a compositioncomprising (a) a DCN1 inhibitor of structural formula (I) and (b) anexcipient and/or pharmaceutically acceptable carrier useful in treatingdiseases or conditions wherein inhibition of DCN1 provides a benefit.

Another embodiment of the present invention is to utilize a compositioncomprising a compound of structural formula (I) and an optional secondtherapeutically active agent in a method of treating an individual for adisease or condition wherein inhibition of DCN provides a benefit.

In a further embodiment, the invention provides for use of a compositioncomprising a DCN1 inhibitor of structural formula (I) and an optionalsecond therapeutic agent for the manufacture of a medicament fortreating a disease or condition of interest, e.g., a cancer.

Still another embodiment of the present invention is to provide a kitfor human pharmaceutical use comprising (a) a container, (b1) a packagedcomposition comprising a DCN inhibitor of structural formula (I), and,optionally, (b2) a packaged composition comprising a second therapeuticagent useful in the treatment of a disease or condition of interest, and(c) a package insert containing directions for use of the composition orcompositions, administered simultaneously or sequentially, in thetreatment of the disease or condition.

Another embodiment is a method of blocking an interaction between DCN1and its binding partners, including, but not limited to, UBC12 andUBC2E, in cells comprising contacting the cells with a compound ofstructural formula (I).

In other embodiments, blocking the interaction between DCN1 and itsbinding partners in cells by contacting the cells with a compound ofstructural formula (I) leads to one or more of (a) selective inhibitionof cullin 3 activity; (b) accumulation of protein substrates of cullin3; (c) upregulation of NRF2, a known cullin 3 substrate; (d) modulationof a set of genes regulated by NRF2; (e) a therapeutic benefit in humandiseases or conditions by modulation of the activity of cullin 3; and(f) a therapeutic benefit in human diseases or conditions by modulationof the activity of NRF2.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts chemical structures of examples of representativenon-covalent and covalent DCN1 inhibitors.

FIG. 2A shows the mass-spectroscopic analyses of DCN1 apo-protein. FIG.2B shows DCN1 apo-protein incubated with covalent DCN1 inhibitor Example4. FIG. 2C is Example 7. FIG. 2D is Example 9. The data showed theformation of a covalent bond between DCN1 protein and each of thesethree representative covalent inhibitors.

FIG. 3 shows the effect of covalent inhibitor Example 9 (see FIG. 1) andnon-covalent inhibitor B (see FIG. 1) on neddylation of cullin 1 andcullin 3 and on the protein level of NRF2 in HepG2 cells. HepG2 cellswere treated as indicated concentrations for 20 h, NRF2, Cullin 1, andCullin 3 proteins were examined by western blotting. GAPDH was used as aloading control. The data showed that the representative covalentinhibitor Example 9 has a much stronger biological activity ininhibition of neddylation of cullin 3 and in increasing the level ofNRF2 protein than the representative non-covalent inhibitor Example B.

FIG. 4 shows the effect of covalent inhibitor Example 21 (see FIG. 1), acovalent, control compound 21b (DI-1859DD, see FIG. 1), and non-covalentinhibitor B (see FIG. 1) on neddylation of cullin 1 and cullin 3 and onthe protein level of NRF2 in immortalized liver THLE2 cell line cells.Immortalized liver THLE2 cell line was treated by dose-ranges ofcovalent DCN1 inhibitor Examples 21 (DI-1859), 21b (DI-1859DD),non-covalent example B (DI-591), a neddylation pan-inhibitor MLN4924 for24 h. The protein levels of neddylated and un-neddylated cullin3,cullin1 and the NRF2 level were examined by western blotting analysis.GAPDH was used as a loading control.

FIG. 5 shows the effect of covalent inhibitor Example 9 (DI-1548) (seeFIG. 1) on the level of Nrf2 protein in mouse liver tissue. Livertissues harvested from C57BL/6 male mice treated with Example 9(DI-1548) at 25 mg/kg via intraperitoneal (IP) injection were lysed withRIAP buffer. The expression level of Nrf2 protein was examined bywestern blotting. GAPDH was used a loading control. A single dose ofExample 9 (DI-1548) effectively increases the level of Nrf2 protein inthe liver tissue.

FIG. 6 shows the effect of covalent inhibitor Example 21 (DI-1859) (seeFIG. 1) on the level of Nrf2 protein in mouse liver tissue. Livertissues harvested from C57BL/6 male mice treated with Example 21(DI-1859) at 25 mg/kg via intraperitoneal (IP) injection were lysed withRIAP buffer. The expression level of Nrf2 protein was examined bywestern blotting. GAPDH was used a loading control. A single dose ofExample 21 (DI-1859) effectively increases the level of Nrf2 protein inthe liver tissue.

FIG. 7 shows the effect of covalent inhibitor Example 22 (DI-1860) (seeFIG. 1) on the level of Nrf2 protein in mouse liver tissue. Livertissues harvested from C57BL/6 male mice treated with Example 22(DI-1860) at 25 mg/kg via intraperitoneal (IP) injection were lysed withRIAP buffer. The expression level of Nrf2 protein was examined bywestern blotting. GAPDH was used a loading control. A single dose ofExample 22 (DI-1860) effectively increases the level of Nrf2 protein inthe liver tissue.

FIG. 8 shows the effect of covalent inhibitor Example 21 (DI-1859) (seeFIG. 1) in effectively reducing the liver tissue damage induced byacetaminophen (APAP) in mice. Mice were treated with APAP, DI-1859,phosphate-buffered saline (PBS), pretreatment with DI-1859, followedwith APAP, or APAP, followed by post-treatment with DI-1859. The serumlevel of alanine transaminase (ALT) was determined for each group ofmice. The data show that DI-1859 effectively blocks or reducesAPAP-induced alanine aminotransferase (ALT) increase in mice, indicatingthat DI-1859 effectively blocks or reduces the liver tissue damageinduced by APAP.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is described in connection with preferredembodiments. However, it should be appreciated that the invention is notlimited to the disclosed embodiments. It is understood that, given thedescription of the embodiments of the invention herein, variousmodifications can be made by a person skilled in the art. Suchmodifications are encompassed by the claims below.

The term “DCN1” as used herein means a protein that functions as aScaffold-Type E3 Ligase for cullin neddylation.

The term “a disease or condition wherein inhibition of DCN1 provides abenefit” pertains to a condition in which DCN1, and/or an action ofDCN1, is important or necessary, e.g., for the onset, progress,expression of that disease or condition, or a disease or a conditionwhich is known to be treated by a DCN1 inhibition. An example of such acondition includes, but is not limited to, an oxidative stress-relateddisease, a neurodegenerative disease, cancer, a cardiovascular disease,or tissue regeneration. One of ordinary skill in the art is readily ableto determine whether a compound treats a disease or condition mediatedby DCN1 for any particular cell type, for example, by assays whichconveniently can be used to assess the activity of particular compounds.

The term “second therapeutic agent” refers to a therapeutic agentdifferent from a DCN1 inhibitor of structural formula (I) and that isknown to treat the disease or condition of interest. For example when acancer is the disease or condition of interest, the second therapeuticagent can be a known chemotherapeutic drug, like taxol, or radiation,for example.

The term “disease” or “condition” denotes disturbances and/or anomaliesthat as a rule are regarded as being pathological conditions orfunctions, and that can manifest themselves in the form of particularsigns, symptoms, and/or malfunctions. As demonstrated below, compoundsof structural formula (I) are potent inhibitors of DCN1 and can be usedin treating diseases and conditions wherein inhibition of DCN1 providesa benefit.

As used herein, the terms “treat,” “treating,” “treatment,” and the likerefer to eliminating, reducing, or ameliorating a disease or condition,and/or symptoms associated therewith. Although not precluded, treating adisease or condition does not require that the disease, condition, orsymptoms associated therewith be completely eliminated. As used herein,the terms “treat,” “treating,” “treatment,” and the like may include“prophylactic treatment,” which refers to reducing the probability ofredeveloping a disease or condition, or of a recurrence of apreviously-controlled disease or condition, in a subject who does nothave, but is at risk of or is susceptible to, redeveloping a disease orcondition or a recurrence of the disease or condition. The term “treat”and synonyms contemplate administering a therapeutically effectiveamount of a compound of structural formula (I) to an individual in needof such treatment.

Within the meaning of the invention, “treatment” includes the treatmentof acute or chronic signs, symptoms, and/or malfunctions. The treatmentcan be orientated symptomatically, for example, to suppress symptoms. Itcan be effected over a short period, be oriented over a medium term, orcan be a long-term treatment, for example within the context of amaintenance therapy.

The term “therapeutically effective amount” or “effective dose” as usedherein refers to an amount of the active ingredient(s) that is(are)sufficient, when administered by a method of the invention, toefficaciously deliver the active ingredient(s) for the treatment ofcondition or disease of interest to an individual in need thereof. Inthe case of a cancer or other oxidative stress-related disorder, thetherapeutically effective amount of the agent may reduce (i.e., retardto some extent and preferably stop) unwanted cellular proliferation;reduce the number of cancer cells; reduce the tumor size; inhibit (i.e.,retard to some extent and preferably stop) cancer cell infiltration intoperipheral organs; inhibit (i.e., retard to some extent and preferablystop) tumor metastasis; inhibit, to some extent, tumor growth; reduceDCN1 interactions in the target cells; and/or relieve, to some extent,one or more of the symptoms associated with the cancer. To the extentthe administered compound or composition prevents growth and/or killsexisting cancer cells, it may be cytostatic and/or cytotoxic.

The term “container” means any receptacle and closure therefor suitablefor storing, shipping, dispensing, and/or handling a pharmaceuticalproduct.

The term “insert” means information accompanying a pharmaceuticalproduct that provides a description of how to administer the product,along with the safety and efficacy data required to allow the physician,pharmacist, and patient to make an informed decision regarding use ofthe product. The package insert generally is regarded as the “label” fora pharmaceutical product.

“Concurrent administration,” “administered in combination,”“simultaneous administration,” and similar phrases mean that two or moreagents are administered concurrently to the subject being treated. By“concurrently,” it is meant that each agent is administered eithersimultaneously or sequentially in any order at different points in time.However, if not administered simultaneously, it is meant that they areadministered to an individual in a sequence and sufficiently close intime so as to provide the desired therapeutic effect and can act inconcert. For example, a DCN1 inhibitor of structural formula (I) can beadministered at the same time or sequentially in any order at differentpoints in time as a second therapeutic agent. A present DCN1 inhibitorand the second therapeutic agent can be administered separately, in anyappropriate form and by any suitable route. When a present DCN1inhibitor and the second therapeutic agent are not administeredconcurrently, it is understood that they can be administered in anyorder to a subject in need thereof. For example, a present DCN1inhibitor can be administered prior to (e.g., 5 minutes, 15 minutes, 30minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks,5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, orsubsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours,96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks,or 12 weeks after) the administration of a second therapeutic agenttreatment modality (e.g., radiotherapy), to an individual in needthereof. In various embodiments, a DCN1 inhibitor of structural formula(I) and the second therapeutic agent are administered 1 minute apart, 10minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hoursapart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hoursto 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hoursapart, no more than 24 hours apart or no more than 48 hours apart. Inone embodiment, the components of the combination therapies areadministered at 1 minute to 24 hours apart.

The use of the terms “a”, “an”, “the”, and similar referents in thecontext of describing the invention (especially in the context of theclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated. Recitation of ranges of values herein areintended to merely serve as a shorthand method of referring individuallyto each separate value falling within the range, unless otherwiseindicated herein, and each separate value is incorporated into thespecification as if it were individually recited herein. The use of anyand all examples, or exemplary language (e.g., “such as”) providedherein, is intended to better illustrate the invention and is not alimitation on the scope of the invention unless otherwise claimed. Nolanguage in the specification should be construed as indicating anynon-claimed element as essential to the practice of the invention.

To date, most small-molecule modulators targeting UPS components containa chemically reactive group and act as covalent inhibitors. Theseinclude FDA-approved Bortezomib (5,6), Carfilzomib (7), and dimethylfumarate (38), and MLN4924 (18), RTA402 and RTA408 (39-41), whichcurrently are in clinical development. Thus the use of covalentinhibitors in this general mechanistic approach to disease modulation iswell precedented, although the abovementioned covalent inhibitors eithertarget the S26 proteasome or KEAP1, whereas compounds of the currentinvention inhibit one very specific step in the ubiquitination pathway,which would be expected to give a very different biological phenotype tothe known irreversible inhibitors of the UPS.

The present invention targets the DCN1-UBC12 protein-protein interactionas a strategy for modulation of protein turnover. DCN1 is a component ofneddylation E3 ligase and plays a role in modulation of the activity ofcullins. The co-crystal structure of DCN1 complexed with UBC12 revealedthat the UBC12 peptide-binding pocket in DCN1 could accommodate asmall-molecule inhibitor for blocking the DCN1-UBC12 protein-proteininteraction. Said co-crystal structures also showed that the portion ofthe inhibitor which is directed towards the solvent binds to DCN1 in amanner which would allow a weak electrophile on that part of theinhibitor to be placed in close proximity, and a suitable orientation,to form a covalent bond with the sulfur atom of Cys119. The presentinvention therefore is directed to a new class of potent covalentinhibitors of the DCN1-UBC12 protein-protein interaction, which form acovalent bond to Cys119 of DCN1.

Recent evidence suggests that the dysfunction of cullin 3 is associatedwith various human diseases, including metabolic disorders,neurodegeneration, and cancer (42-44). Modulation of cullin 3 thereforecan have a therapeutic potential for the treatment of human diseases.Compared to the global inhibition of neddylation of all cullins byMLN4924, a compound of structural formula (I) is a selective inhibitorof the neddylation of cellular CUL3. A compound of structural formula(I) increases the level of NRF2 protein, a well known substrate ofcullin 3, leading to upregulation of two detoxification enzymes NQO1 andHO1. In comparison, MLN4924, a NAE inhibitor, globally increases theabundance of all cullin-targeted proteins examined. Therefore, compoundsof structural formula (I) serves as excellent chemical probes for astudy of cullin 3 and its role in different biological processes andhuman diseases.

As the master regulator of antioxidant responses, NRF2 regulates about200 genes involved in cytoprotection, lipid metabolism, and genetranscription. Activation of NRF2 can have a therapeutic benefit againstvarious oxidative stress-related diseases, including cancer,neurodegenerative disease, cardiovascular disease, acute lung injury,chronic obstructive pulmonary diseases, autoimmune disease, andinflammation (36, 45, 46, 47). One NRF2 inducer, dimethyl fumarate, hasrecently been approved by the FDA as first-line therapy forrelapsing-remitting multiple sclerosis (MS) (38). Another series of NRF2inducers under clinical development are synthetic derivatives ofoleanoic acid (39,40). A common mechanism of these compounds is thatthey are covalent modulators targeting Keap1. In comparison, a compoundof structural formula (I) activates NRF2 by blocking the DCN1-UBC12protein-protein interaction and selectively inhibiting the activity ofcullin 3, thus engaging a different mechanism of action. The DCN1inhibitors of the present invention therefore are useful in thetreatment of a variety of diseases and conditions in subjects in need ofsuch treatment.

The present invention is directed to compounds having a structuralformula (I).

wherein;

Q is C═O, C═S or SO₂;

Ar₁ is a five or six-membered aromatic or heteroaromatic ring or abicyclic aromatic or heteroaromatic ring having 8-12 atoms, including upto four heteroatoms chosen from N, O and S, in a chemically stablearrangement, optionally substituted with up to four R₂ substituents;

T is halogen, SS—C₁₋₆ lower alkyl, pentafluorophenoxy,tetrafluorophenoxy:

X is selected from a bond, CR₇R₈, CR₇R₈NR₁₂, CR₇R₈NR₁₂CO,CR₇R₈NR₁₂CONR₁₂, CR₇R₈NR₁₂SO₂, CR₇R₈O, CR₇R₈S(O)_(x) CONR₁₂;

Y is selected from C₁₋₆ alkylidyl, C₃₋₆ cycloalkylidyl, C₄₋₇heterocloalkylidyl, arylene, heteroarylene, aryl(m)ethylene,heteroaryl(m)ethylene, fused C₅₋₈ bicycloalkylidyl or C₅₋₉spirocycloalkylidyl;

Or Y and R₉ are taken together with the nitrogen atom to which they areattached to form a heterocyclic or heteroaryl ring of four to sevenmembers, optionally including any chemically stable combination of oneto three groups selected from O, C═O, N, NR₅ and S;

Z is

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl;

R₂ are independently selected from the group consisting of halo, CN, N₃,CF₃, NO₂, H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₂₋₆ alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆cycloalkyl, substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substitutedC₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, phenyl, substituted phenyl,monocyclic heteroaryl, substituted monocyclic heteroaryl, OR₅, NR₃R₄,COOR₅, CONR₃R₄;

R₃ and R₄, independently, are selected from the group consisting ofhydrogen, C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl,heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₁₋₆ alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, or are taken together with the nitrogen atom towhich they are attached to form a ring of four to seven members,optionally including any chemically stable combination of one to threeO, C═O, NR₅ and S;

R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂, C₁₋₆alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl,C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, each optionally substituted with up to threesubstituents independently selected from halo, hydroxy, oxo, thio,thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₄₋₇ heterocycloalkyl, aryl, and heteroaryl;

R₆ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, C₂₋₆ alkynyl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl. C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆ alkylaryl, heteroaryl, C₁₋₆alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl and C₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl;

R₇ and R₈ may be independently H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl,C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl, C₂₋₆ alkynyl, substituted C₂₋₆alkynyl, or taken together with the C atom to which they are attached,form a carbonyl group, a thionyl group, an oxime, a hydrazone, C₃₋₆cycloalkyl, substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substitutedC₄₋₆ cycloalkenyl or C₄₋₇ heterocycloalkyl:

R₉ is selected from the group consisting of H, C₁₋₆ alkyl, substitutedC₁₋₆ alkyl, C₃₋₆ alkenyl, substituted C₃₋₆ alkenyl, C₃₋₆ alkynyl,substituted C₃₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, phenyl, substitutedphenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl or C₄₋₇heterocycloalkyl:

R₁₀ is H, F, Cl, CF₃, CHF₂, (CH₂)_(n)NR₃R₄, CH₂SO₂R₁₂, CH₂OCOR₁₂, CN orR₁₂;

R_(11e) is H, R₁₂, (CH₂)_(n)R₂, CF₂(CH₂)_(x)R₂, COR₅, CO₂R₅ or CONR₃R₄;

R_(11z) is H, F, Cl, CF₃, CHF₂, CF₂R₁₂ or R₁₂;

Or R_(11e) and R_(11z) may be taken together with the sp² carbon atom towhich both are bonded to form an alicyclic ring of 4 to 7 members whereone of the ring atoms may be NR₁₂, O, or S(O)_(x), optionallysubstituted with halogen, oxo, OH, OR₅, NR₃R₄;

Or R_(11e) and R_(11z) taken together may be R_(11e)R_(11z)C═, formingan allenyl group;

Or R₁₀ and R_(11e) may be taken together with the sp² C atoms to whichthey are attached to form a partially saturated carbocyclic orheterocyclic ring of 5-7 atoms, with up to two of the ring atoms beingO, S(O)_(x), NR₁₂, and said ring may be substituted with hydroxy, oxo,C₁₋₆ alkoxy,

R_(11t) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl, C₄₋₇heterocycloalkyl, CH₂NR₃R₄;

R₁₂ is H or C₁₋₆ alkyl, either straight chain or branched;

n is 1, 2 or 3;

x is 0, 1, or 2;

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

An embodiment of the invention involves a compound of formula (I)

wherein;

Q is C═O;

Ar₁ is a five or six-membered aromatic or heteroaromatic ring or abicyclic aromatic or heteroaromatic ring having 8-12 atoms, including upto four heteroatoms chosen from N, O and S, in a chemically stablearrangement, optionally substituted with up to four R₂ substituents;

X is selected from a bond, CR₇R₈, CR₇R₈NR₁₂, CR₇R₈NR₁₂CO,CR₇R₈NR₁₂CONR₁₂, CR₇R₈NR₁₂SO₂, CR₇R₈O, CR₇R₈S(O)x CONR₁₂;

Y is selected from C₁₋₆ alkylidyl, C₃₋₆ cycloalkylidyl, C₄₋₇heterocloalkylidyl, arylene, heteroarylene, aryl(m)ethylene,heteroaryl(m)ethylene;

Or Y and R₉ are taken together with the nitrogen atom to which they areattached to form a heterocyclic or heteroaryl ring of four to sevenmembers, optionally including any chemically stable combination of oneto three groups selected from O, C═O, N, NR₅ and S;

Z is

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl;

R₂ are independently selected from the group consisting of halo, CN, N₃,CF₃, NO₂, H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₂₋₆ alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆cycloalkyl, substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substitutedC₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, phenyl, substituted phenyl,monocyclic heteroaryl, substituted monocyclic heteroaryl, OR₅, NR₃R₄,COOR₅, CONR₃R₄;

R₃ and R₄, independently, are selected from the group consisting ofhydrogen, C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl,heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₁₋₆ alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, or are taken together with the nitrogen atom towhich they are attached to form a ring of four to seven members,optionally including any chemically stable combination of one to threeO, C═O, NR₅ and S;

R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂, C₁₋₆alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl,C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, each optionally substituted with up to threesubstituents independently selected from halo, hydroxy, oxo, thio,thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₄₋₇ heterocycloalkyl, aryl, and heteroaryl;

R₆ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, C₂₋₆ alkynyl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl. C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆ alkylaryl, heteroaryl, C₁₋₆alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl and C₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl;

R₇ and R₈ may be independently H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl,C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl, C₂₋₆ alkynyl, substituted C₂₋₆alkynyl, or taken together with the C atom to which they are attached,form a carbonyl group, a thionyl group, an oxime, a hydrazone, C₃₋₆cycloalkyl, substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substitutedC₄₋₆ cycloalkenyl or C₄₋₇ heterocycloalkyl:

R₉ is selected from the group consisting of H, C₁₋₆ alkyl, substitutedC₁₋₆ alkyl, C₃₋₆ alkenyl, substituted C₃₋₆ alkenyl, C₃₋₆ alkynyl,substituted C₃₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, phenyl, substitutedphenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl or C₄₋₇heterocycloalkyl:

R₁₀ is H, F, CF₃, CHF₂, (CH₂)_(n)NR₃R₄, CN or R₁₂;

R_(11e) is H, R₁₂, (CH₂)_(n)R₂, CF₂(CH₂)_(x)R₂, COR₅, CO₂R₅ or CONR₃R₄;

R_(11z) is H, F, Cl, CF₃, CHF₂;

Or R_(11e) and R_(11z) may be taken together with the sp² carbon atom towhich both are bonded to form an alicyclic ring of 4 to 7 members whereone of the ring atoms may be NR₁₂, O, or S(O)_(x), optionallysubstituted with halogen, oxo, OH, OR₅, NR₃R₄;

Or R₁₀ and R_(11e) may be taken together with the sp² C atoms to whichthey are attached to form a partially saturated carbocyclic orheterocyclic ring of 5-7 atoms, with up to two of the ring atoms beingO, S(O)_(x), NR₁₂, and said ring may be substituted with hydroxy, oxo,C₁₋₆ alkoxy,

R_(11t) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocycloalkyl, CH₂NR₃R₄;

R₁₂ is H or C₁₋₆ alkyl, either straight chain or branched;

T is halogen;

n is 1, 2 or 3;

x is 0, 1, or 2;

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In another embodiment of the invention the compound is a compound offormula (1)

wherein;

Ar₁ is a five or six-membered aromatic or heteroaromatic ring or abicyclic aromatic or heteroaromatic ring having 8-12 atoms, including upto four heteroatoms chosen from N, O and S, in a chemically stablearrangement, optionally substituted with up to four R₂ substituents;

T is halogen:

X—Y is selected from the group consisting of:

such that Ar₂ is monocyclic arylene or heteroarylene;

Z is

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl;

R₂ are independently selected from the group consisting of halo, CN, N₃,CF₃, NO₂, H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₂₋₆ alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆cycloalkyl, substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substitutedC₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, phenyl, substituted phenyl,monocyclic heteroaryl, substituted monocyclic heteroaryl, OR₅, NR₃R₄,COOR₅, CONR₃R₄;

R₃ and R₄, independently, are selected from the group consisting ofhydrogen, C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl,heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₁₋₆ alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, or are taken together with the nitrogen atom towhich they are attached to form a ring of four to seven members,optionally including any chemically stable combination of one to threeO, C═O, NR₅ and S;

R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂, C₁₋₆alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl,C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, each optionally substituted with up to threesubstituents independently selected from halo, hydroxy, oxo, thio,thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₄₋₇ heterocycloalkyl, aryl, and heteroaryl;

R₆ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, C₂₋₆ alkynyl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl. C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆ alkylaryl, heteroaryl, C₁₋₆alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl and C₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl;

R₉ is selected from the group consisting of H, C₁₋₆ alkyl, substitutedC₁₋₆ alkyl, C₃₋₆ alkenyl, substituted C₃₋₆ alkenyl, C₃₋₆ alkynyl,substituted C₃₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, phenyl, substitutedphenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl or C₄₋₇heterocycloalkyl:

R₁₀ is H, (CH₂)_(n)NR₃R₄, CN or R₁₂;

R_(11e) is H, R₁₂, or (CH₂)_(n)NR₃R₄;

R_(11z) is H, F, Cl, CF₃, CHF₂;

Or R₁₀ and R_(11e) may be taken together with the sp² C atoms to whichthey are attached to form a partially saturated carbocyclic orheterocyclic ring of 5-7 atoms, with up to two of the ring atoms beingO, S(O)_(x), NR₁₂, and said ring may be substituted with hydroxy, oxo,C₁₋₆ alkoxy,

R_(11t) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocycloalkyl, CH₂NR₃R₄;

R₁₂ is H or C₁₋₆ alkyl, either straight chain or branched;

l is 2-4;

m is 2-6;

n is 1, 2 or 3;

x is independently 0, 1, or 2;

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In another embodiment of the invention the compound is a compound offormula (1)

wherein;

Q is C═O;

Ar₁ is a five or six-membered aromatic or heteroaromatic ring or abicyclic aromatic or heteroaromatic ring having 8-12 atoms, including upto four heteroatoms chosen from N, O and S, in a chemically stablearrangement, optionally substituted with up to four R₂ substituents;

X, Y and R₉ are taken together with the nitrogen atom to which they areattached to form a ring which selected from the group consisting of:

-   -   Z is

R₁

is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt, NH-cyclopropyl, OMe, OEt,O-cyclopropyl;

R₂ are independently selected from the group consisting of halo, CN, N₃,CF₃, NO₂, H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₂₋₆ alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆cycloalkyl, substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substitutedC₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, phenyl, substituted phenyl,monocyclic heteroaryl, substituted monocyclic heteroaryl, OR₅, NR₃R₄,COOR₅, CONR₃R₄;

R₃ and R₄, independently, are selected from the group consisting ofhydrogen, C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl,heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₁₋₆ alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, or are taken together with the nitrogen atom towhich they are attached to form a ring of four to seven members,optionally including any chemically stable combination of one to threeO, C═O, NR₅ and S;

R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂, C₁₋₆alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl,C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, each optionally substituted with up to threesubstituents independently selected from halo, hydroxy, oxo, thio,thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₄₋₇ heterocycloalkyl, aryl, and heteroaryl;

R₆ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, C₂₋₆ alkynyl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl. C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆ alkylaryl, heteroaryl, C₁₋₆alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl and C₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl;

R₁₀ is H, (CH₂)_(n)NR₃R₄, CN or R₁₂;

R_(11e) is H, R₁₂, or (CH₂)_(n)NR₃R₄;

R_(11z) is H, F, Cl, CF₃, CHF₂;

Or R₁₀ and R_(11e) may be taken together with the sp² C atoms to whichthey are attached to form a partially saturated carbocyclic orheterocyclic ring of 5-7 atoms, with up to two of the ring atoms beingO, S(O)_(x), NR₁₂, and said ring may be substituted with hydroxy, oxo,C₁₋₆ alkoxy,

R_(11t) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocycloalkyl, CH₂NR₃R₄;

R₁₂ is H or C₁₋₆ alkyl, either straight chain or branched;

T is halogen:

m is 2-6;

n is 1, 2 or 3;

x is independently 0, 1, or 2;

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In certain preferred embodiment of the invention the compound is acompound of formula (1)

wherein;

Q is C═O;

Ar₁ is a five or six-membered aromatic or heteroaromatic ring or abicyclic aromatic or heteroaromatic ring having 8-12 atoms, including upto four heteroatoms chosen from N, O and S, in a chemically stablearrangement, optionally substituted with up to four R2 substitutents;

X—Y is selected from the group consisting of:

such that Ar₂ is monocyclic arylene or heteroarylene;

Z is

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl;

R₂ are independently selected from the group consisting of halo, CN, N₃,CF₃, NO₂, H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₂₋₆ alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆cycloalkyl, substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substitutedC₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, phenyl, substituted phenyl,monocyclic heteroaryl, substituted monocyclic heteroaryl, OR₅, NR₃R₄,COOR₅, CONR₃R₄;

R₃ and R₄, independently, are selected from the group consisting ofhydrogen, C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl,heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₁₋₆ alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, or are taken together with the nitrogen atom towhich they are attached to form a ring of four to seven members,optionally including any chemically stable combination of one to threeO, C═O, NR₅ and S;

R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂, C₁₋₆alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl,C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, each optionally substituted with up to threesubstituents independently selected from halo, hydroxy, oxo, thio,thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₄₋₇ heterocycloalkyl, aryl, and heteroaryl;

R₆ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, C₂₋₆ alkynyl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl. C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆ alkylaryl, heteroaryl, C₁₋₆alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl and C₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl;

R₉ is H;

R₁₀ is H, CN or CH₂NR₃R₄;

R_(11e) and R_(11z) are H or one may be R₁₂;

R₁₂ is H or C₁₋₆ alkyl, either straight chain or branched;

l is 2-4;

m is 2-6;

n is 1, 2 or 3;

x is independently 0, 1, or 2;

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In certain preferred embodiments of the invention the compound is acompound of formula (1)

wherein;

Q is C═O;

Ar₁ is a five or six-membered aromatic or heteroaromatic ring or abicyclic aromatic or heteroaromatic ring having 8-12 atoms, including upto four heteroatoms chosen from N, O and S, in a chemically stablearrangement, optionally substituted with up to four R₂ substituents;

X, Y and R₉ are taken together with the nitrogen atom to which they areattached to form a ring which selected from the group consisting of:

Z is

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl;

R₂ are independently selected from the group consisting of halo, CN, N₃,CF₃, NO₂, H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₂₋₆ alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆cycloalkyl, substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substitutedC₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, phenyl, substituted phenyl,monocyclic heteroaryl, substituted monocyclic heteroaryl, OR₅, NR₃R₄,COOR₅, CONR₃R₄;

R₃ and R₄, independently, are selected from the group consisting ofhydrogen, C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl,heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₁₋₆ alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, or are taken together with the nitrogen atom towhich they are attached to form a ring of four to seven members,optionally including any chemically stable combination of one to threeO, C═O, NR₅ and S;

R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂, C₁₋₆alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl,C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, each optionally substituted with up to threesubstituents independently selected from halo, hydroxy, oxo, thio,thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₄₋₇ heterocycloalkyl, aryl, and heteroaryl;

R₆ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, C₂₋₆ alkynyl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl. C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆ alkylaryl, heteroaryl, C₁₋₆alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl and C₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl;

R₁₀ is H, CN or CH2NR3R4;

R_(11e) and R_(11z) are H or one may be R₁₂;

R₁₂ is H or C₁₋₆ alkyl, either straight chain or branched;

m is 2-6;

n is 1, 2 or 3;

x is independently 0, 1, or 2;

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In certain more preferred embodiments the compound is of Formula (II)

wherein:

Ar₁ is a five or six-membered aromatic or heteroaromatic ring or abicyclic aromatic or heteroaromatic ring having 8-12 atoms, including upto four heteroatoms chosen from N, O and S, in a chemically stablearrangement, optionally substituted with up to four R₂ substituents;

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl;

R₂ are independently selected from the group consisting of halo, CN, N₃,CF₃, NO₂, H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₂₋₆ alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆cycloalkyl, substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substitutedC₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, phenyl, substituted phenyl,monocyclic heteroaryl, substituted monocyclic heteroaryl, OR₅, NR₃R₄,COOR₅, CONR₃R₄;

R₃ and R₄, independently, are selected from the group consisting ofhydrogen, C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl,heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₁₋₆ alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, or are taken together with the nitrogen atom towhich they are attached to form a ring of four to seven members,optionally including any chemically stable combination of one to threeO, C═O, NR₅ and S;

R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂, C₁₋₆alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl,C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, each optionally substituted with up to threesubstituents independently selected from halo, hydroxy, oxo, thio,thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₄₋₇ heterocycloalkyl, aryl, and heteroaryl;

R₆ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, C₂₋₆ alkynyl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl. C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆ alkylaryl, heteroaryl, C₁₋₆alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl and C₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl;

R₉ is selected from the group consisting of H, C₁₋₆ alkyl, substitutedC₁₋₆ alkyl, C₃₋₆ alkenyl, substituted C₃₋₆ alkenyl, C₃₋₆ alkynyl,substituted C₃₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, phenyl, substitutedphenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl or C₄₋₇heterocycloalkyl:

R₁₀ is H, F, Cl, CF₃, CHF₂, (CH₂)_(n)NR₃R₄, CH₂SO₂R₁₂, CH₂OCOR₁₂, CN orR₁₂;

R_(11e) is H, R₁₂, (CH₂)_(n)R₂, CF₂(CH₂)_(x)R₂, COR₅, CO₂R₅ or CONR₃R₄;

R_(11z) is H, F, Cl, CF₃, CHF₂, CF₂R₁₂ or R₁₂;

Or R_(11e) and R_(11z) may be taken together with the sp² carbon atom towhich both are bonded to form an alicyclic ring of 4 to 7 members whereone of the ring atoms may be NR₁₂, O, or S(O)_(x), optionallysubstituted with halogen, oxo, OH, OR₅, NR₃R₄;

Or R_(11e) and R_(11z) taken together may be R_(11e)R_(11z)C═, formingan allenyl group;

Or R₁₀ and R_(11e) may be taken together with the sp² C atoms to whichthey are attached to form a partially saturated carbocyclic orheterocyclic ring of 5-7 atoms, with up to two of the ring atoms beingO, S(O)_(x), NR₁₂, and said ring may be substituted with hydroxy, oxo,C₁₋₆ alkoxy,

R_(11t) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl, C₄₋₇heterocycloalkyl, CH₂NR₃R₄;

R₁₂ is H or C₁₋₆ alkyl, either straight chain or branched;

n is 1, 2 or 3;

x is 0, 1, or 2;

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In some highly preferred embodiments the compound is of Formula (III)

wherein:

Ar₁ is a five or six-membered aromatic or heteroaromatic ring or abicyclic aromatic or heteroaromatic ring having 8-12 atoms, including upto four heteroatoms chosen from N, O and S, in a chemically stablearrangement, optionally substituted with up to four R₂ substituents;

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl;

R₂ are independently selected from the group consisting of halo, CN, N₃,CF₃, NO₂, H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₂₋₆ alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆cycloalkyl, substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substitutedC₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, phenyl, substituted phenyl,monocyclic heteroaryl, substituted monocyclic heteroaryl, OR₅, NR₃R₄,COOR₅, CONR₃R₄;

R₃ and R₄, independently, are selected from the group consisting ofhydrogen, C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl,heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₁₋₆ alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, or are taken together with the nitrogen atom towhich they are attached to form a ring of four to seven members,optionally including any chemically stable combination of one to threeO, C═O, NR₅ and S;

R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂, C₁₋₆alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl,C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl,C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl,C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl,aroyl, heteroaroyl, each optionally substituted with up to threesubstituents independently selected from halo, hydroxy, oxo, thio,thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₄₋₇ heterocycloalkyl, aryl, and heteroaryl;

R₆ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇ heterocycloalkyl, C₂₋₆ alkynyl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl. C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆ alkylaryl, heteroaryl, C₁₋₆alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl and C₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl;

R₉ is selected from the group consisting of H, C₁₋₆ alkyl, substitutedC₁₋₆ alkyl, C₃₋₆ alkenyl, substituted C₃₋₆ alkenyl, C₃₋₆ alkynyl,substituted C₃₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, phenyl, substitutedphenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl or C₄₋₇heterocycloalkyl:

n is 1, 2 or 3;

x is 0, 1, or 2;

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In some more highly preferred embodiments the compound is of Formula(III)

wherein:

Ar₁ is benzothiazol-2-yl, benzoxazol-2-yl, naphth-2-yl,4-methyl-5-phenylthiazole, 4-methyl-5-phenyloxazole andimidazo[1,2-a]pyrid-2-yl, whereby each 6-membered aromatic ring in maybe substituted with up to two R₂ substituents selected from C₁₋₆ loweralkyl, CF₃, and halogen;

R₁ is methyl, ethyl, methylamino, cyclopropyl, isopropyl or n-propyl;

R₃ and R₄, independently, are selected from the group consisting of C₁₋₆alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, or are taken togetherwith the nitrogen atom to which they are attached to form a ring of fourto seven members, optionally including any chemically stable combinationof one to three O, C═O, NR₅ and S;

R₅ is C₁₋₄ alkyl, C₁₋₄ acyl, C₂₋₄ hydroxyalkyl, C₁₋₂ alkoxy-C₂₋₄ alkyl,oxetan-3-yl, oxolan-3-yl, oxan-4-yl, N-methylazetidin-3-yl,N-methylpyrrolidin-3-yl or N-methylpiperidin-4-yl;

R₆ is benzyl, isopropyl, [R]- or [S]-2-butyl, 3-pentyl, cyclopentyl,cyclohexyl, cyclohexylmethyl, cyclpentylmethyl, 4-tetrahydrofuranyl orisopropyl;

R₉ is H, C₁₋₄ alkyl, C₂₋₄ hydroxyalkyl, C₁₋₂ alkoxy-C₂₋₄ alkyl,oxetan-3-yl, oxolan-3-yl, oxan-4-yl, N-methylazetidin-3-yl,N-methylpyrrolidin-3-yl or N-methylpiperidin-4-yl;

In some preferred embodiments, Ar₁ can be, but is not limited to,

The above examples illustrate embodiments having a single R₂substituent, it is understood that Ar1 groups can be free of an R₂substituent or contain one to four R₂ substituents.

In some embodiments, R₁ can be, but is not limited to,

In some embodiments, R₆ can be, but is not limited to

In some embodiments R₉ can be H

In some embodiments X can be a bond or CH₂ or CO or CONR₁₂.

In some embodiments Y can be methylidyl, arylene, heteroarylene,arylmethylene, heteroarylmethylene,

In some embodiments R₉ can be H

In some embodiments Z can be

In certain preferred embodiments in a compound of Formula (1):

Ar₁ is selected from 2-benzothienyl, 2-naphthyl, 2-benzoxazolyl,2-imidazo[1,2-a]pyridinyl or 4-methyl-5-(3-halophenyl)thiazol-2-yl,wherein there are one or R₂ substituents on the B-ring of the bicycle,selected from the group chloro, bromo. methyl, CF₃, methyl ethylisopropyl and cyclopropyl.

R₁ is selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl,methylamino and methoxy.

R₆ is selected from [S]-butyl, cyclopentyl, cyclohexyl,4-tetrahydropyranyl, benzyl, cyclohexylmethyl, 2-, 3-, and4-pyridylmethylene, and trans-4-aminomethylcyclohexylmethylenyl.

X is a bond, CH₂, CH₂NH or CH₂O.

Y is CH₂, arylene, hetroarylene

Or R₉ and Y taken together are, azetidin-3-yl, pyrrolidin-3-yl,pipidin-3-yl, pipidin-4-yl.

Z is

In more preferred embodiments wherein compounds are of Formula (I):

Ar₁ is benzothiazol-2-yl, imidazo[1,5-a]pyridine-2-yl, or5-phenylthiazol-2-yl or 2-naphthyl.

R₁ is methyl, ethyl, isopropyl, cyclopropyl or methylamino.

Wherein there are one or R₂ substituents on the B-ring of the bicycle,selected from the group chloro, bromo. methyl, CF₃, methyl ethylisopropyl and cyclopropyl.

R₆ is cyclopentyl, cyclohexyl, 4-tetrahydropyranyl, [S]-2-butyl, benzyl,3-tetrahydrofuranyl, cyclohexylmethyl.

X is a bond;

Y is CH₂;

Z is

The compounds of formula (I) inhibit DCN1 and are useful in thetreatment of a variety of diseases and conditions. In particular, thecompounds of structural formula (I) are used in methods of treating adisease or condition wherein inhibition of DCN1 provides a benefit, forexample, oxidative stress-related disease, including cancers,neurodegenerative diseases, cardiovascular diseases, acute lung injury,autoimmune diseases, chronic obstructive pulmonary disease,inflammation, and multiple sclerosis. The method comprises administeringa therapeutically effective amount of a compound of structural formula(I) to an individual in need thereof. The present methods also encompassadministering a second therapeutic agent to the individual in additionto the compound of structural formula (I). The second therapeutic agentis selected from drugs known as useful in treating the disease orcondition afflicting the individual in need thereof, e.g., achemotherapeutic agent and/or radiation known as useful in treating aparticular cancer.

As used herein, the term “halo” is defined as encompassing fluoro,chloro, bromo, and iodo.

The term “hydroxy” is defined as —OH.

The term “alkoxy” is defined as —OR, wherein R is alkyl.

The term “amino” is defined as —NH₂, and the term “alkylamino” and“dialkylamino” are defined as —NR₂, wherein at least one R is alkyl andthe second R is alkyl or hydrogen.

The term “nitro” is defined as —NO₂.

The term “cyano” is defined as —CN.

The term “trifluoromethyl” is defined as —CF₃.

The term “trifluoromethoxy” is defined as —OCF₃.

The term “azido” is defined as —N₃.

The term “carboxyl” is defined as —CO₂R, where R is H or alkyl.

The term “carbamoyl” is defined as —CON(R)₂, wherein R, independently,is H or alkyl.

The term “alkylthio” is defined as —SR, wherein R is alkyl.

The term “alkylsulfinyl” is defined as —S(O)R, wherein R is alkyl.

The term “alkylsulfonyl” is defined as —S(O₂)R, wherein R is alkyl.

The term “alkylsulfonamido” is defined as —S(O₂)NHR, wherein R is alkyl.

The term “alkylsulfamoyl” is defined as —NHS(O₂)R, wherein R is alkyl.

The term “allyl” is defined as CH₂═CHCH₂—.

The term “proparyl” is defined as CH═CCH₂—.

As used herein, groups such as

is an abbreviation for

is an abbreviation for

Lower alkyl is C₁₋₆alkyl, either straight chain or branched. Examplesinclude methyl, ethyl, n-propyl i-propyl, n-butyl, [R]- or [S]-isobutyl,t-butyl, n-pentyl, [R]- or [S]-2-pentyl, 3 pentyl, [R]- or[S]-3-methylbut-2-yl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, n-hexyl,[R]- or [S]-2-hexyl, [R]- or [S]-3-hexyl, [R]- or [S]-2-methylpent-1-yl,[R]- or [S]-2-methylpent-3-yl, [R]- or [S]-4-methylpent-2-yl,2-methylpent-2-yl, [RR]-, [RS]-, [SR]- or [SS]-3-methylpent-2-yl, [R]-or [S]-3-methylpent-1-yl, 4-methylpent-1-yl, 2-methylpent-2-yl,3-methylpent-3-yl, 2,2-dimethylbut-1-yl, 3,3-dimethylbut-1-yl, [R]- or[S]-3,3-dimethylbut-2-yl, or [R]- or [S]-2,3-dimethylbut-1-yl,2,3-dimethylbut-2-yl.

Lower alkenyl is C₂₋₆alkenyl, either straight chain or branched.Examples include ethenyl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl, E- and Z-but-1-en-1-yl, E- or Z-but-2-en-1-yl,but-3-en-1-yl, [R]- or [S]-but-3-en-2-yl, E- or Z-but-2-en-2-yl,2-methylprop-1-en-1-yl, 2-methylprop-2-en-1-yl, E- or Z-pent-1-en-1-yl,E- or Z-pent-2-en-1-yl, E- or Z-pent-2-en-2-yl, E- or Z-pent-2-en-3-yl,E- or Z-pent-3-en-1-yl, [R]- or [S]-E- or [R]- or [S]—Z-pent-3-en-2-yl,pent-4-en-1-yl, [R]- or [S]-pent-1-en-3-yl, [R]- or [S]-pent-4-en-2-yl,E- or Z-2-methylbut-1-en-1-yl, [R]- or [S}-2-methylbut-3-en-1-yl,2-methylbut-3-en-2-yl, 3-methylbut-1-en-2-yl, [R]- or[S}-3-methylbut-1-en-1-yl, [R]- or [S}-2-methylbut-2-en-1-yl,3-methylbut-2-en-1-yl, 3-methylbut-2-en-2-yl, [R]- or[S}-3-methylbut-3-en-2-yl, 3-methylbut-3-en-1-yl, 2-ethylprop-2-en-1-yl,E- or Z-hex-1-en-1-yl, hex-1-en-2-yl, [R]- or [S]-hex-1-en-3-yl, [R]- or[S]-hex-5-en-3-yl, [R]- or [S]-hex-5-en-2-yl, hex-5-en-1-yl, E- orZ-hex-2-en-1-yl, E- or Z-hex-2-en-2-yl, E- or Z-hex-2-en-3-yl, [R]- or[S]-E- or [R]- or [S]—Z-hex-4-en-3-yl, [R]- or [S]-E- or [R]- or[S]—Z-hex-4-en-2-yl, E- or Z-hex-4-en-1-yl, E- or Z-hex-3-en-1-yl, [R]-or [S]-E- or [R]- or [S]—Z-hex-3-en-2-yl, E- or Z-hex-3-en-3-yl, E- orZ-2-methylpent-1-en-1-yl, 2-propylprop-2-en-1-yl, [R]- or[S}-2-methylpent-1-en-3-yl, [R]- or [S}-4-methylpent-4-en-2-yl,4-methylpent-4-en-1-yl, E- or Z-2-methylpent-2-en-1-yl,2-methylpent-2-en-3-yl, [R]- or [S]-4-methylpent-3-en-2-yl,4-methylpent-3-en-1-yl, [R]- or [S]-E- or [R]- or[S]—Z-2-methylpent-2-en-1-yl, E- or Z-2-methylpent-3-en-2-yl, E- orZ-2-methylpent-3-en-3-yl, E- or Z-4-methylpent-2-en-2-yl, E- orZ-4-methylpent-2-en-1-yl, [R]- or [S]-2-methylpent-4-en-1-yl, [R]- or[S]-4-methylpent-1-en-3-yl, E- or Z-4-methylpent-1-en-1-yl,2-methylpent-4-en-2-yl, 4-methylpent-1-en-2-yl, E- orZ-3,3-dimethylbut-1-en-1-yl, 3,3-dimethylbut-1-en-2-yl,2,2-dimethylbut-3-en-1-yl, E- or Z-2,3-dimethylbut-1-en-1-yl,2,3-dimethylbut-3-en-2-yl, [R]- or [S]-2,3-dimethylbut-3-en-1-yl,2-(1methylethyl)prop-2-en-1-yl, or 2,3-dimethylbyt-2-en-1-yl.

Lower alkynyl is C₂₋₆alkynyl, either straight chain or branched.Examples include ethylnyl, prop-1-yn-1-yl, prop-2-yn-1-yl,but-1-yn-1-yl, but-2-yn-1-yl, but-3-yn-1-yl, [R]- or [S]-but-3-yn-2-yl,3-methylbut-1-yn-1-yl, 2-methylbut-3-yn-3-yl, [R]- or[S]-2-methylbut-3-yn-1-yl, hex-1-yn-1-yl, [R]- or [S]-hex-1-yn-3-yl,[R]- or [S]-hex-5-yn-3-yl, [R]- or [S]-hex-5-yn-2-yl, hex-5-yn-1-yl,hex-2-yn-1-yl, [R]- or [S]-hex-4-yn-3-yl, [R]- or [S]-hex-4-yn-2-yl,hex-4-yn-1-yl, hex-3-yn-1-yl, [R]- or [S]-hex-3-yn-2-yl,4-methylpent-1-yn-1-yl, [R]- or [S]-4-methylpent-1-yn-3-yl,2-methylpent-4-yn-2-yl, [R]- or [S]-2-methylpent-4-yn-1-yl, [R]- or[S]-3-methylpent-1-yn-1-yl, [R]- or [S]-3-methylpent-1-yn-3-yl, [RR]-,[RS]-, [SR]- or [SS]-3-methylpent-4-yn-2-yl, [R]- or[S]-3-methylpent-4-yn-1-yl, [R]- or [S]-2-ethylbut-3-yn-1-yl,3,3-dimethylbut-1-yn-1-yl, or 3,3-dimethylbut-3-yn-1-yl.

Lower cycloalkyl is C₃₋₈ cycloalkyl. Examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

Lower cycloalkenyl is C₄₋₈ cycloalkenyl. Examples includecyclobut-1-en-1-yl, [R]- or [S]-cyclobut-2-en-1-yl, cyclopent-1-en-1-yl,[R]- or [S]-cyclopent-2-en-1-yl, cyclopent-3-en-1-yl,cyclohex-1-en-1-yl, [R]- or [S]-cyclohex-2-en-1-yl, [R]- or[S]-cyclohex-3-en-1-yl, cyclohept-1-en-1-yl, [R]- or[S]-cyclohept-2-en-1-yl, [R]- or [S]-cyclohept-3-en-1-yl,cyclohept-4-en-1-yl, cyclooct-1-en-1-yl, [R]- or [S]-cyclooct-2-en-1-yl,[R]- or [S]-cyclooct-3-en-1-yl, and [R]- or [S]-cyclooct-4-en-1-yl,

Heterocyclo defines rings of four to eight atoms which contain betweenone and three heteroatoms, chosen from O, NR₅ and S(O)_(x), with theproviso that the species obey the valence laws, and be chemicallystable. Rings may be linked at any position allowed by the valence laws,including N, N+ and SIV or SVI heteroatoms. Representative examplesinclude azetidine, oxetane, thietane, oxolane, pyrrolidine, thiolane,piperidine, oxane, thiane, azepane, oxapane, azocane, oxacane, thiacane,pyrazolidine, imidazolidine, 1,3-dioxolane, 1,2-dithiolane,1,3-dithiolane, 1,2-diazinane, 1,3-diazinane, piperazine, 1,3-dioxane,1,4-dioxane, 1,2-dithiane, 1,3-dithiane, 1,4-dithiane, 1,2-diazepane,1,3-diazepane, 1,4-diazepane, 1,3-dioxepane, 1,4-dioxepane,1,2-dithiepane, 1,3-dithiepane, 1,4-dithiepane, 1,2-diazocane,1,3-diazocane, 1,4-diazocane, 1,5-diazocane, 1,3-dioxocane,1,4-dioxocane, 1,5-dioxocane, 1,2-dithiocane, 1,3-dithiocane,1,4-dithiocane, 1,5-dithiocane, 1,2-oxazolidine, 1,3-oxazolidine,1,3-thiazolidine, 1,3-oxathialane, 1,2-oxazane, 1,3-oxazane, morpholine,1,3-thiazane, thiomorpholine, 1,3-oxathiane, 1,4-oxathiane,1,2-oxazepane, 1,3-oxazepane, 1,4-oxazepane, 1,3-oxathiepane,1,4-oxathiepane, 1,3-thiazepane, 1,4-thiazepane, 1,2-oxazocane,1,3-oxazocane, 1,4-oxazocane, 1,5-oxazocane, 1,3-oxathiocane,1,4-oxathiocane, 1,5-oxathiocane, 1,3-thiazocane, 1,4-thiazocane,1,5-thiazocane, 1,2,5-triazepane, 1,4,5-oxadiazepane,1,2,5-oxadiazepane, 1,4,5-dioxazepane, 1,4,5-thiadiazepane,1,2,5-triazocane, 1,4,5-oxadiazocane, 1,2,5-oxadiazocane,1,2,6-oxadiazocane, 1,4,8-dioxazocane, 1,5,8-dioxazocane,1,3,6-dioxazocane, 1,3,6-oxathiazocane, 1,4,5-oxathiazocane,1,5,6-oxathiazocane, 1,4,5-oxadiazocane, 1,3,6-dioxathiocane,1,3,7-dioxathiocane, 1,3,6-oxadithiocane, 1,4,7-oxadithiocane,1,3,6-oxadithiocane, 1,3,6-trithiocane, 1,2-thiazolane-1,1,dioxide,1,2,5-thiadiazolane-1,1,dioxide, 1,2-thiazinane-1,1,dioxide,1,2,6-thiadiazinane-1,1,dioxide, 1,4-dithiane-1,1-dioxide,1,4-dithiane-1,1,4,4-tetroxide, 1,4-oxathiane-1,1-dioxide,1,4-thiazinane-1,1-dioxide, 1,4-oxathiepane-1,1-dioxide,1,2-thiazepane-1,1-dioxide, 1,4-thiazepane 1,1-dioxide,1,4-dithiepane-1,1-dioxide, 1,4-dithiepane-1,1,4,4-tetroxide,1,2,5-thiadiazepane-1,1-dioxide, 1,2,7-thiadiazepane-1,1-dioxide,1,4,7-oxathiazepane-1,1-dioxide, 1,4,7-dithiazepane-1,1-dioxide,1,4,7-dithiazepane-1,1,4,4-tetroxide, 1,4-dithiocane-1,1-dioxide,1,5-dithiocane-1,1-dioxide, 1,4-dithiocane-1,1,4,4-tetroxide,1,5-dithiocane-1,1,5,5-tetroxide, 1,4,8-oxathiazocane-1,1-dioxide,1,5,8-oxathiazocane-1,1-dioxide, 1,4,5-oxathiazocane-1,1-dioxide,1,5,6-oxathiazocane-1,1-dioxide, 1,4,8-thiadiazocane-1,1-dioxide,1,5,8-thiadiazocane-1,1-dioxide, 1,4,5-thiadiazocane-1,1-dioxide,1,2,8-thiadiazocane-1,1-dioxide, 1,3,6-oxadithiocane-1,1-dioxide,1,3,6-oxadithiocane-1,1,3,3-tetroxide, 1,3,6-dithiazocane-1,1-dioxide,1,3,6-dithiazocane-1,1,3,3-tetroxide, 1,3,8-dithiazocane-1,1-dioxide,1,3,8-dithiazocane-1,1,3,3-tetroxide, 1,4,8-dithiazocane-1,1-dioxide,1,4,8-dithiazocane-1,1,4,4-tetroxide, 1,5,2-dithiazocane-1,1-dioxide,1,5,2-dithiazocane-1,1,5,5-tetroxide, 1,3,6-trithiocane-6,6-dioxide,1,3,6-trithiocane-1,1-dioxide, 1,3,6-trithiocane-1,1,3,3-tetroxide,1,3,6-trithiocane-1,1,6,6-tetroxide, and1,3,6-trithiocane-1,1,3,3,6,6-hexoxide.

Bicycloalkyl is bicyclic structures of 5-12 carbon atoms, the two ringsof which may be have fused, bridged, or spiro junctions. All chemicallyfeasible diastereoisomers and enantiomers are included in thedefinition, as illustrated for bicyclo[2.1.0]pentyl below, where thepoint of attachment is marked by 1.

Heterobicyclo includes the structures defined for bicycloalkyl, wherebetween one and four carbon atoms have been replaced with heteroatoms,chosen from O, NR₅ and S(O)_(x), with the proviso that the species obeythe valence laws, and be chemically stable, and with the further provisothat no heteroatoms are placed in three membered rings, or more than oneheteroatom is placed in a four membered ring, unless explicitly stated.Rings may be linked at any position allowed by the valence laws,including N, N+ and SIV or SVI heteroatoms.

Aryl is phenyl, indenyl, indenyl, naphthyl, azulenyl, fluorenyl,anthracenyl, phenanthrenyl, all of which may be optionally substitutedwith up to four substituents independently chosen from, halogen, loweralkyl, lower alkenyl, lower alkynyl, OH, lower alkoxy, lower acyloxy,amino, lower acylamino, lower alkylamino, lower dialkylamino, lowerS(O)xalkyl, trifluoromethyl, carbaldehyde, carboxy, lower carboxyalkyl,carboxamido, lower carboxamidoalkyl, and lower carboxamidodialkyl,

Heteroaryl is pyrrole, pyrazole, imidazole, 1,2,3-triazole,1,2,4-triazole, tetrazole, furan, oxazole, isoxazole, thiophene,thiazole, isothiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole,1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, pyridine,pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine,1,3,5-triazine, or 1,2,4,5-tetrazine.

Polycycloheteroaryl is a fused bicyclic or tricyclic aromatic ringsystem of 8 to 12 atoms, at least one of which but not more than five(for bicycles), or seven (for tricycles) must O, N, NR, or S. Suchpolycyclic rings may include pyrrolo[2,3-b]pyrrole,pyrrolo[3,2-b]pyrrole, pyrrolo[2,3-c]pyrrole, pyrrolo[3,4-c]pyrrole,pyrrolo[2,3-b]furan, pyrrolo[3,2-b]furan, pyrrolo[3,4-b]furan,pyrrolo[2,3-c]furan, pyrrolo[3,4-c]furan, pyrrolo[2,3-b]thiophene,pyrrolo[3,4-b]thiophene, pyrrolo[3,2-b]thiophene, pyrrolo[2,3-c]thiophene, pyrrolo[3,4-c] thiophene, furano[2,3-b]furan,furano[3,2-b]furan, furano[2,3-c]furan, furano[3,4-c]furan,furano[2,3-b]thiophene, furano[3,4-b]thiophene, furano[3,2-b]thiophene,furano[2,3-c] thiophene, furano[3,4-c] thiophene,thieno[2,3-b]thiophene, thieno[3,2-b]thiophene, thieno[2,3-c]thiophene,thieno[3,4-c]thiophene, pyrrolo[2,3-c]pyrazole, pyrrolo[3,2-c]pyrazole,pyrrolo[3,4-c]pyrazole, furano[2,3-c]pyrazole, furano[3,2-c]pyrazole,furano[3,4-c]pyrazole, thieno[2,3-c]pyrazole, thieno[3,2-c]pyrazole,thieno[3,4-c]pyrazole, pyrrolo[2,3-d]imidazole, pyrrolo[3,4-d]imidazole,furano[2,3-d]imidazole, furano[3,4-d]imidazole, thieno[2,3-d]imidazole,thieno[3,4-d]imidazole, pyrrolo[2,3-d]-1,2,3-triazole,pyrrolo[3,4-d]-1,2,3-triazole, furano[2,3-d]-1,2,3-triazole,furano[3,4-d]-1,2,3-triazole, thieno[2,3-d]-1,2,3-triazole,thieno[3,4-d]-1,2,3-triazole, pyrrolo[3,2-d]isoxazole,pyrrolo[2,3-c]isoxazole, pyrrolo[3,4-d]isoxazole,pyrrolo[3,4-c]isoxazole, pyrrolo[2,3-d]isoxazole,pyrrolo[3,2-c]isoxazole, furano[3,2-d]isoxazole, furano[2,3-c]isoxazole,furano[3,4-d]isoxazole, furano[3,4-c]isoxazole, furano[2,3-d]isoxazole,furano[3,2-c]isoxazole, thieno[3,2-d]isoxazole, thieno[2,3-c]isoxazole,thieno[3,4-d]isoxazole, thieno[3,4-c]isoxazole, thieno[2,3-d]isoxazole,thieno[3,2-c]isoxazole, pyrrolo[3,2-d]oxazole, pyrrolo[2,3-d]oxazole,pyrrolo[3,4-d]oxazole, furano[3,2-d]oxazole, furano[2,3-d]oxazole,furano[3,4-d]oxazole, thieno[3,2-d]oxazole, thieno[2,3-d]oxazole,thieno[3,4-d]oxazole, pyrrolo[3,2-d]isothiazole,pyrrolo[2,3-c]isothiazole, pyrrolo[3,4-d]isothiazole,pyrrolo[3,4-c]isothiazole, pyrrolo[2,3-d]isothiazole,pyrrolo[3,2-c]isothiazole, furano[3,2-d]isothiazole,furano[2,3-c]isothiazole, furano[3,4-d]isothiazole,furano[3,4-c]isothiazole, furano[2,3-d]isothiazole,furano[3,2-c]isothiazole, thieno[3,2-d]isothiazole,thieno[2,3-c]isothiazole, thieno[3,4-d]isothiazole,thieno[3,4-c]isothiazole, thieno[2,3-d]isothiazole,thieno[3,2-c]isothiazole, pyrrolo[3,2-d]thiazole,pyrrolo[2,3-d]thiazole, pyrrolo[3,4-d]thiazole, furano[3,2-d]thiazole,furano[2,3-d]thiazole, furano[3,4-d]thiazole, thieno[3,2-d]thiazole,thieno[2,3-d]thiazole, thieno[3,4-d]thiazole,pyrrolo[3,2-d]-1,2,3-thiadiazole, pyrrolo[2,3-d]-1,2,3-thiadiazole,pyrrolo[3,4-d]-1,2,3-thiadiazole, furano[3,2-d]-1,2,3-thiadiazole,furano[2,3-d]-1,2,3-thiadiazole, furano[3,4-d]-1,2,3-thiadiazole,thieno[3,2-d]-1,2,3-thiadiazole, thieno[2,3-d]-1,2,3-thiadiazole,thieno[3,4-d]-1,2,3-thiadiazole, pyrrolo[2,3-c]-1,2,5-oxadiazole,pyrrolo[3,4-c]-1,2,5-oxadiazole, furano[2,3-c]-1,2,5-oxadiazole,furano[3,4-c]-1,2,5-oxadiazole, thieno[2,3-c]-1,2,5-oxadiazole,thieno[3,4-c]-1,2,5-oxadiazole, pyrrolo[2,3-c]-1,2,5-thiadiazole,pyrrolo[3,4-c]-1,2,5-thiadiazole, furano[2,3-c]-1,2,5-thiadiazole,furano[3,4-c]-1,2,5-thiadiazole, thieno[2,3-c]-1,2,5-thiadiazole,thieno[3,4-c]-1,2,5-thiadiazole, pyrazolo[3,4-c]pyrazole,pyrazolo[4,3-c]pyrazole, imidazo[4,5-c]pyrazole,pyrazolo[4,3-d]triazole, imidazo[4,5-d]triazole,pyrazolo[3,4-c]isoxazole, pyrazolo[4,3-d]isoxazole,pyrazolo[4,3-c]isoxazole, pyrazolo[3,4-d]isoxazole,pyrazolo[4,3-d]oxazole, pyrazolo[3,4-d]oxazole, imidazo[4,5-c]isoxazole,imidazo[5,4-d]isoxazole, isoxazolo[3,4-d]triazole,oxazolo[4,5-d]triazole, pyrazolo[3,4-c]isothiazole,pyrazolo[4,3-d]isothiazole, pyrazolo[4,3-c]isothiazole,pyrazolo[3,4-d]isothiazole, pyrazolo[4,3-d]thiazole,pyrazolo[3,4-d]thiazole, imidazo[4,5-c]isothiazole,imidazo[5,4-d]isothiazole, isothiazolo[3,4-d]triazole,thiazolo[4,5-d]triazole, isoxazolo[3,4-c]isoxazole,isoxazolo[4,5-d]isoxazole, isoxazolo[5,4-c]isoxazole,isoxazolo[4,3-c]isoxazole, isoxazolo[4,5-c]isoxazole,isoxazolo[5,4-d]isoxazole, isoxazolo[3,4-d]oxazole,isoxazolo[4,3-d]oxazole, isoxazolo[4,5-d]oxazole,isoxazolo[5,4-d]oxazole, oxazolo[4,5-d]oxazole, oxazolo[5,4-d]oxazole,isoxazolo[3,4-c]isothiazole, isoxazolo[4,5-d]isothiazole,isoxazolo[5,4-c]isothiazole, isoxazolo[3,4-d]isothiazole,isoxazolo[4,3-c]isothiazole, isoxazolo[4,5-c]isothiazole,isoxazolo[3,4-d]isothiazole, isoxazolo[5,4-d]isothiazole,isoxazolo[3,4-d]thiazole, oxazolo[5,4-d]isothiazole,isoxazolo[4,3-d]thiazole, oxazolo[4,5-d]isothiazole,isoxazolo[4,5-d]thiazole, oxazolo[5,4-c]isothiazole,isoxazolo[5,4-d]thiazole, oxazolo[4,5-c]isothiazole,oxazolo[4,5-d]thiazole, oxazolo[5,4-d]thiazole,isothiazolo[3,4-c]isothiazole, isothiazolo[4,5-d]isothiazole,isothiazolo[5,4-c]isothiazole, isothiazolo[4,3-c]isothiazole,isothiazolo[4,5-c]isothiazole, isothiazolo[5,4-d]isothiazole,isothiazolo[3,4-d]thiazole, isothiazolo[4,3-d]thiazole,isothiazolo[4,5-d]thiazole, isothiazolo[5,4-d]thiazole,thiazolo[4,5-d]thiazole, thiazolo[5,4-d]thiazole,pyrazolo[5,4-d]-1,2,3-thiadiazole, pyrazolo[3,4-d]-1,2,3-thiadiazole,imidazo[4,5-d]-1,2,3-thiadiazole, isoxazolo[4,3-d]-1,2,3-thiadiazole,isothiazolo[4,3-d]-1,2,3-thiadiazole,isoxazolo[4,5-d]-1,2,3-thiadiazole,isothiazolo[4,5-d]-1,2,3-thiadiazole,isoxazolo[3,4-d]-1,2,3-thiadiazole,isothiazolo[3,4-d]-1,2,3-thiadiazole,isoxazolo[5,4-d]-1,2,3-thiadiazole,isothiazolo[5,4-d]-1,2,3-thiadiazole, oxazolo[4,5-d]-1,2,3-thiadiazole,thiazolo[4,5-d]-1,2,3-thiadiazole, oxazolo[5,4-d]-1,2,3-thiadiazole,thiazolo[5,4-d]-1,2,3-thiadiazole, pyrazolo[4,3-d]-1,2,5-thiadiazole,pyrazolo[4,3-d]-1,2,5-oxadiazole, isoxazolo[4,3-d]-1,2,5-thiadiazole,isothiazolo[4,3-d]-1,2,5-thiadiazole, isoxazolo[4,3-d]-1,2,5-oxadiazole,isothiazolo[4,3-d]-1,2,5-oxadiazole, isoxazolo[4,5-d]-1,2,5-thiadiazole,isothiazolo[4,5-d]-1,2,5-thiadiazole, isoxazolo[4,5-d]-1,2,5-oxadiazole,isothiazolo[4,5-d]-1,2,5-oxadiazole, imidazo[4,5-d]-1,2,5-thiadiazole,imidazo[4,5-d]-1,2,5-oxadiazole, oxazolo[4,5-d]-1,2,5-thiadiazole,thiazolo[4,5-d]-1,2,5-thiadiazole, oxazolo[4,5-d]-1,2,5-oxadiazole,thiazolo[4,5-d]-1,2,5-oxadiazole, pyrrolo[1,2-b] thiazole,imidazo[1,2-b]pyrazole, imidazo[1,2-a]imidazole, imidazo[2,1-b]thiazole,imidazo[2,1-c]-1,2,4-triazole, thiazolo[2,3-c]-1,2,4-triazole,imidazo[1,2-b]-1,2,4-triazole, thiazolo[3,2-b]-1,2,4-triazole,oxazolo[3,2-b]-1,2,4-triazole, thiazolo[3,2-b]-1,2,4-triazole,triazolo[1,5-b]1,3,4-oxadiazole, triazolo[1,5-b]1,3,4-thiadiazole,indole, isoindole, benzofuran, isobenzofuran, benzothiophene,isobenzothiophene, indolizine, indazole, benzimidazole, benzoxazole,benzoisooxazole, benzothiazole, benzoisothiazole,pyrazolo[1,5-a]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine,benzotriazole, benzo-1,2,5-oxadiazole benzo-1,2,3-thiadiazole,benzo-1,2,5-thiadiazole, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine,pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, furano[2,3-b]pyridine,furano [2,3-c]pyridine, furano [3,2-c]pyridine, furano [3,2-b]pyridine,thieno[2,3-b]pyridine, thieno [2,3-c]pyridine, thieno [3,2-c]pyridine,thieno [3,2-b]pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo [4,3-c]pyridine, pyrazolo [4,3-b]pyridine,isoxazolo[5,4-b]pyridine, isoxazolo[5,4-c]pyridine,isoxazolo[4,5-c]pyridine, isoxazolo[4,5-b]pyridine,isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine,isothiazolo[4,5-c]pyridine, isothiazolo[4,5-b]pyridine,imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine, oxazolo[5,4-b]pyridine,oxazolo[5,4-c]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-b]pyridine,thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine,thiazolo[4,5-c]pyridine, thiazolo[4,5-b]pyridine,1,2,3-thiadiazolo[5,4-b]pyridine, 1,2,3-thiadiazolo[5,4-c]pyridine,1,2,3-thiadiazolo[4,5-c]pyridine, 1,2,3-thiadiazolo[4,5-b]pyridine,1,2,5-thiadiazolo[4,5-c]pyridine, 1,2,5-thiadiazolo[4,5-b]pyridine,1,2,5-oxadiazolo[4,5-c]pyridine, 1,2,5-oxadiazolo[4,5-b]pyridine,pyrazolo[2,3-b]pyridazine, imidazo[3,4-b]pyridazine,imidazo[3,2-b]pyridazine, pyrazolo[2,3-c]pyrimidine,imidazo[3,4-c]pyrimidine, imidazo[1,2-c]pyrimidine,pyrazolo[5,1-c]pyrazine, imidazo[5,1-c]pyrazine, imidazo[1,2-c]pyrazine,pyrazolo[2,3-a]pyrimidine, imidazo[3,4-a]pyrimidine,imidazo[3,2-a]pyrimidine, pyrrolo[2,3-c]pyridazine,furano[2,3-c]pyridazine, thieno[2,3-c]pyridazine,pyrrolo[3,2-c]pyridazine, furano[3,2-c]pyridazine,thieno[3,2-c]pyridazine, pyrrolo[2,3-d]pyridazine,furano[2,3-d]pyridazine, thieno[2,3-dpyridazine,pyrrolo[2,3-d]pyrimidine, furano[2,3-d]pyrimidine,thieno[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine,furano[3,2-d]pyrimidine, thieno[3,2-d]pyrimidine,pyrrolo[2,3-b]pyrazine, furano[2,3-b]pyrazine, thieno[2,3-b]pyrazine,1,2,3-triazolo[1,5-b]pyridazine, 1,2,4-triazolo[4,3-b]pyridazine,1,2,4-triazolo[1,5-b]pyridazine, 1,2,3-triazolo[1,5-c]pyrimidine,1,2,4-triazolo[4,3-c]pyrimidine, 1,2,4-triazolo[1,5-c]pyrimidine,1,2,3-triazolo[1,5-a]pyrazine, 1,2,4-triazolo[4,3-a]pyrazine,1,2,4-triazolo[1,5-a]pyrazine, 1,2,3-triazolo[1,5-a]pyrimidine,1,2,4-triazolo[4,3-a]pyrimidine, 1,2,4-triazolo[1,5-a]pyrimidine,pyrazolo[3,4-c]pyridazine, isothiazolo[5,4-c]pyridazine,isoxazolo[5,4-c]pyridazine, imidazo[4,5-c]pyridazine,thiazolo[5,4-c]pyridazine, oxazolo[5,4-c]pyridazine,pyrazolo[3,4-d]pyrimidine, isothiazolo[5,4-d]pyrimidine,isoxazolo[5,4-d]pyrimidine, imidazo[4,5-d]pyrimidine,thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine,pyrazolo[4,3-d]pyrimidine, isothiazolo[4,5-d]pyrimidine,isoxazolo[4,5-d]pyrimidine, thiazolo[4,5-d]pyrimidine,oxazolo[4,5-d]pyrimidine, pyrazolo[3,4-b]pyrazine,isothiazolo[4,5-b]pyrazine, isoxazolo[4,5-b]pyrazine,imidazo[4,5-b]pyrazine, thiazolo[4,5-b]pyrazine, oxazolo[4,5-b]pyrazine,1,2,3-triazolo[1,5-b]-1,2,4-triazine,1,2,3-triazolo[5,1-f]-1,2,4-triazine,1,2,3-triazolo[1,5-d]-1,2,4-triazine,1,2,3-triazolo[5,1-c]-1,2,4-triazine,1,2,4-triazolo[5,1-f]-1,2,4-triazine,1,2,4-triazolo[3,4-f]-1,2,4-triazine,1,2,4-triazolo[4,3-d]-1,2,4-triazine,1,2,4-triazolo[1,5-d]-1,2,4-triazine,1,2,3-triazolo[1,5-a]-1,3,5-triazine,1,2,4-triazolo[1,5-a]-1,3,5-triazine,1,2,4-triazolo[4,3-a]-1,3,5-triazine,1,2,4-triazolo[3,4-c]-1,2,4-triazine,1,2,4-triazolo[5,1-c]-1,2,4-triazine, 1,2,3-triazolo[4,5-c]pyridazine,1,2,3-triazolo[4,5-d]pyrimidine, 1,2,3-triazolo[4,5-b]pyrazine,1,2,3-triazolo[4,5-d]pyridazine, 1,2,3-thiadiazolo[4,5-d]pyridazine,1,2,3-thiadiazolo[4,5-d]pyrimidine, 1,2,3-thiadiazolo[5,4-d]pyrimidine,1,2,5-thiadiazolo[3,4-d]pyrimidine, 1,2,5-oxadiazolo[3,4-d]pyrimidine,1,2,5-oxadiazolo[3,4-d]pyridazine, 1,2,5-thiadiazolo[3,4-d]pyridazine,1,2,5-oxadiazolo[3,4-d]pyrazine, 1,2,5-thiadiazolo[3,4-d]pyrazine,pyrazolo[3,4-d]-1,2,3-triazine, pyrazolo[4,3-e]-1,2,4-triazine,pyrazolo[3,4-e]-1,2,4-triazine, pyrazolo[4,3-d]-1,2,3-triazine,imidazo[4,5-d]-1,2,3-triazine, imidazo[4,5-e]-1,2,4-triazine,oxazolo[4,5-e]-1,2,4-triazine, oxazolo[5,4-e]-1,2,4-triazine,oxazolo[4,5-d]-1,2,3-triazine, thiazolo[5,4-d]-1,2,3-triazine,thiazolo[5,4-e]-1,2,4-triazine, thiazolo[4,5-e]-1,2,4-triazine,isothiazolo[4.5-d]-1,2,3-triazine, isoxazolo[4.5-d]-1,2,3-triazine,isoxazolo[5,4-d]-1,2,3-triazine, isoxazolo[4.5-e]-1,2,4-triazine,isoxazolo[4.3,d]-1,2,3-triazine, isothiazolo[4.3,d]-1,2,3-triazine,quinoline, isoquinoline, cinnoline, quinazoline, phthalazine,quinoxaline, 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine,1,8-naphthyridine, 2,5-naphthyridine, 2,6-naphthyridine,2,7-naphthyridine, pyrido[2,3-c]pyridazine, pyrido[3,4-c]pyridazine,pyrido[4,3-c]pyridazine, pyrido[3,2-c]pyridazine,pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine,pyrido[4,3-d]pyrimidine, pyrido[3,2-d]pyrimidine,pyrido[2,3-d]pyridazine, pyrido[3,4-d]pyridazine, pyrido[2,3-b]pyrazine,pyrido[3,4-b]pyrazine, pyridazo[3,4-c]pyridazine,pyridazo[4,5-c]pyridazine, pyridazo[4,5-c]pyridazine,pyrimido[5,4-c]pyridazine, pyrimido[4,5-c]pyridazine,pyrazino[2,3-c]pyridazine, pyrimido[4,5-d]pyridazine,pyrazino[2,3-d]pyridazine, pyrimido[4,5-d]-1,2,3-triazine,pyrimido[5,4-d]-1,2,3-triazine, pyrimido[4,5-e]-1,2,4-triazine,pyrimido[5,4-e]-1,2,4-triazine, and pyrazino[2,3-e]-1,2,4-triazine.Tricycles can be made by a 1,2-fusion of phenyl, or any of the earliermentioned heteroaryl rings, to two adjacent, non-bridging atoms of anyof the abovementioned bicycles, with the provisos that the valence rulesbe obeyed, the resultant tricycle be an aromatic entity, and that thefused tricycle contains no more than seven total heteroatoms.

All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl,aryl, heteroaryl, and alkoxy groups can be optionally substituted with1-3 groups independently selected from halo, hydroxy, alkoxy, oxo, loweracyloxy, amino, alkylamino, dialkylamino, alkylthio, alkylsulfonyl,heterocyclyl, aryl, heteroaryl, with the provisos that no carbon-linkedsubstituent may iterate more than twice in total, and that thesubstituents produce chemically stable molecules.

All stereoisomers of compounds are claimed, except where a specificstereochemistry is delineated at a chiral center.

All analogues where hydrogen is replaced with deuterium are alsoclaimed.

Additionally, salts of the compounds of structural formula (I) also areincluded in the present invention and can be used in the methodsdisclosed herein. The present invention further includes all possiblestereoisomers and geometric isomers of the compounds of structuralformula (I). The present invention includes both racemic compounds andoptically active isomers. When a compound of structural formula (I) isdesired as a single enantiomer, it can be obtained either by resolutionof the final product or by stereospecific synthesis from eitherisomerically pure starting material or use of a chiral auxiliaryreagent, for example, see Z. Ma et al., Tetrahedron: Asymmetry, 8(6),pages 883-888 (1997). Resolution of the final product, an intermediate,or a starting material can be achieved by any suitable method known inthe art. Additionally, in situations where tautomers of the compounds ofstructural formula (I) are possible, the present invention is intendedto include all tautomeric forms of the compounds.

Various compounds of the present invention can exist as salts.Pharmaceutically acceptable salts of compounds of structural formula (I)often are preferred in the methods of the invention. As used herein, theterm “pharmaceutically acceptable salts” refers to salts or zwitterionicforms of the compounds of structural formula (I). Salts of compounds offormula (I) can be prepared during the final isolation and purificationof the compounds or separately by reacting the compound with an acid orbase having a suitable counterion. The pharmaceutically acceptable saltsof compounds of structural formula (I) can be acid addition salts formedwith pharmaceutically acceptable acids. Examples of acids which can beemployed to form pharmaceutically acceptable salts include inorganicacids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, andphosphoric, and organic acids such as oxalic, maleic, succinic, andcitric. Nonlimiting examples of salts of compounds of the inventioninclude, but are not limited to, the hydrochloride, hydrobromide,hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate,hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate,bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,glycerolphosphate, hemisulfate, heptanoate, hexanoate, formate,succinate, fumarate, maleate, ascorbate, isethionate, salicylate,methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate,trifluoroacetate, phosphate, glutamate, bicarbonate,paratoluenesulfonate, undecanoate, lactate, citrate, tartrate,gluconate, methanesulfonate, ethanedisulfonate, benzene sulphonate, andp-toluenesulfonate salts. In addition, available amino groups present inthe compounds of the invention can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides. Inlight of the foregoing, any reference to compounds of the presentinvention appearing herein is intended to include compounds ofstructural formula (I), as well as pharmaceutically acceptable salts,thereof.

Specific compounds of the present invention, and representative bindingaffinity to DCN1 protein, include, but are not limited to, compoundshaving a structure set forth below in Table 1.

Binding affinity to DCN1 Example Structure (IC₅₀, nM) 1

205 2

153 3

156 4

41.6 5

80.7 6

135 7

37.4 8

99.8 9

66.5 10

ND 11

ND 12

292 13

ND 14

ND 15

ND 16

ND 17

ND 18

ND 19

ND 20

360 21

<150 22

<150 23

<150 24

<150 25

<150 26

<150 27

<150 28

<150 29

<150 30

<150 31

<150 32

<150 33

<150 34

<150 35

<300 36

<150 37

<200 38

<150 39

<150

Representative compounds of the current invention include, but are notlimited to the following.

The present invention provides DCN1 inhibitors of structural formula (I)for the treatment of a variety of diseases and conditions whereininhibition of DCN1 provides a beneficial effect. In one embodiment, thepresent invention relates to a method of treating an individualsuffering from a disease or condition wherein inhibition of the DCN1provides a benefit comprising administering a therapeutically effectiveamount of a compound of structural formula (I) to an individual in needthereof.

The method of the present invention can be accomplished by administeringa compound of structural formula (I) as the neat compound or as apharmaceutical composition. Administration of a pharmaceuticalcomposition, or neat compound of structural formula (I), can beperformed during or after the onset of the disease or condition ofinterest. Typically, the pharmaceutical compositions are sterile, andcontain no toxic, carcinogenic, or mutagenic compounds that would causean adverse reaction when administered. Further provided are kitscomprising a compound of structural formula (I) and, optionally, asecond therapeutic agent useful in the treatment of diseases andconditions wherein inhibition of DCN1 provides a benefit, packagedseparately or together, and an insert having instructions for usingthese active agents.

In many embodiments, a compound of structural formula (I) isadministered in conjunction with a second therapeutic agent useful inthe treatment of a disease or condition wherein inhibition of DCN1provides a benefit. The second therapeutic agent is different from thecompound of structural formula (I). A compound of structural formula (I)and the second therapeutic agent can be administered simultaneously orsequentially to achieve the desired effect. In addition, the compound ofstructural formula (I) and second therapeutic agent can be administeredfrom a single composition or two separate compositions.

The second therapeutic agent is administered in an amount to provide itsdesired therapeutic effect. The effective dosage range for each secondtherapeutic agent is known in the art, and the second therapeutic agentis administered to an individual in need thereof within such establishedranges.

A compound of structural formula (I) and the second therapeutic agentcan be administered together as a single-unit dose or separately asmulti-unit doses, wherein the compound of structural formula (I) isadministered before the second therapeutic agent or vice versa. One ormore dose of the compound of structural formula (I) and/or one or moredose of the second therapeutic agent can be administered. The compoundsof structural formula (I) therefore can be used in conjunction with oneor more second therapeutic agents, for example, but not limited to,anticancer agents. It is envisioned that one or more dose of a DCN1inhibitor of structural formula (I) and/or one or more dose of a secondtherapeutic agent can be administered.

A present DCN1 inhibitor can be used in the treatment of a variety ofdiseases and conditions, including for example, metabolic disorders,oxidative stress-related diseases, cardiovascular diseases,neurodegenerative diseases, viral infections, inflammation, acute lunginjury, chronic obstructive pulmonary diseases, metabolic disorders,multiple sclerosis, inflammation, multiple myeloma, and autoimmunedisease.

The diseases and conditions that can be treated in accordance to theinvention include, for example, cancers. A variety of cancers can betreated including, but not limited to: carcinomas, including bladder(including accelerated and metastatic bladder cancer), breast, colon(including colorectal cancer), kidney, liver, lung (including small andnon-small cell lung cancer and lung adenocarcinoma), ovary, prostate,testes, genitourinary tract, lymphatic system, rectum, larynx, pancreas(including exocrine pancreatic carcinoma), esophagus, stomach, gallbladder, cervix, thyroid, renal, and skin (including squamous cellcarcinoma); hematopoietic tumors of lymphoid lineage, includingleukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia,B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkinslymphoma, hairy cell lymphoma, histiocytic lymphoma, and Burkettslymphoma, hematopoietic tumors of myeloid lineage, including acute andchronic myelogenous leukemias, myelodysplastic syndrome, myeloidleukemia, and promyelocytic leukemia; tumors of the central andperipheral nervous system, including astrocytoma, neuroblastoma, glioma,and schwannomas; tumors of mesenchymal origin, including fibrosarcoma,rhabdomyoscarcoma, and osteosarcoma; and other tumors, includingmelanoma, xenoderma pigmentosum, keratoactanthoma, seminoma, thyroidfollicular cancer, teratocarcinoma, renal cell carcinoma (RCC),pancreatic cancer, myeloma, myeloid and lymphoblastic leukemia,neuroblastoma, and glioblastoma.

Additional forms of cancer treatable by the DCN1 inhibitors of thepresent invention include, for example, adult and pediatric oncology,growth of solid tumors/malignancies, myxoid and round cell carcinoma,locally advanced tumors, metastatic cancer, human soft tissue sarcomas,including Ewing's sarcoma, cancer metastases, including lymphaticmetastases, squamous cell carcinoma, particularly of the head and neck,esophageal squamous cell carcinoma, oral carcinoma, blood cellmalignancies, including multiple myeloma, leukemias, including acutelymphocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocyticleukemia, chronic myelocytic leukemia, and hairy cell leukemia, effusionlymphomas (body cavity based lymphomas), thymic lymphoma lung cancer(including small cell carcinoma, cutaneous T cell lymphoma, Hodgkin'slymphoma, non-Hodgkin's lymphoma, cancer of the adrenal cortex,ACTH-producing tumors, nonsmall cell cancers, breast cancer, includingsmall cell carcinoma and ductal carcinoma), gastrointestinal cancers(including stomach cancer, colon cancer, colorectal cancer, and polypsassociated with colorectal neoplasia), pancreatic cancer, liver cancer,urological cancers (including bladder cancer, such as primarysuperficial bladder tumors, invasive transitional cell carcinoma of thebladder, and muscle-invasive bladder cancer), prostate cancer,malignancies of the female genital tract (including ovarian carcinoma,primary peritoneal epithelial neoplasms, cervical carcinoma, uterineendometrial cancers, vaginal cancer, cancer of the vulva, uterine cancerand solid tumors in the ovarian follicle), malignancies of the malegenital tract (including testicular cancer and penile cancer), kidneycancer (including renal cell carcinoma, brain cancer (includingintrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas,and metastatic tumor cell invasion in the central nervous system), bonecancers (including osteomas and osteosarcomas), skin cancers (includingmalignant melanoma, tumor progression of human skin keratinocytes, andsquamous cell cancer), thyroid cancer, retinoblastoma, neuroblastoma,peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms'stumors, gall bladder cancer, trophoblastic neoplasms,hemangiopericytoma, and Kaposi's sarcoma.

In the present method, a therapeutically effective amount of a compoundof structural formula (I), typically formulated in accordance withpharmaceutical practice, is administered to a human being in needthereof. Whether such a treatment is indicated depends on the individualcase and is subject to medical assessment (diagnosis) that takes intoconsideration signs, symptoms, and/or malfunctions that are present, therisks of developing particular signs, symptoms and/or malfunctions, andother factors.

A compound of structural formula (I) can be administered by any suitableroute, for example by oral, buccal, inhalation, sublingual, rectal,vaginal, intracisternal or intrathecal through lumbar puncture,transurethral, nasal, percutaneous, i.e., transdermal, or parenteral(including intravenous, intramuscular, subcutaneous, intracoronary,intradermal, intramammary, intraperitoneal, intraarticular, intrathecal,retrobulbar, intrapulmonary injection and/or surgical implantation at aparticular site) administration. Parenteral administration can beaccomplished using a needle and syringe or using a high pressuretechnique.

Pharmaceutical compositions include those wherein a compound ofstructural formula (I) is administered in an effective amount to achieveits intended purpose. The exact formulation, route of administration,and dosage is determined by an individual physician in view of thediagnosed condition or disease. Dosage amount and interval can beadjusted individually to provide levels of a compound of structuralformula (I) that is sufficient to maintain therapeutic effects.

Toxicity and therapeutic efficacy of the compounds of structural formula(I) can be determined by standard pharmaceutical procedures in cellcultures or experimental animals, e.g., for determining the maximumtolerated dose (MTD) of a compound, which defines as the highest dosethat causes no toxicity in animals. The dose ratio between the maximumtolerated dose and therapeutic effects (e.g. inhibiting of tumor growth)is the therapeutic index. The dosage can vary within this rangedepending upon the dosage form employed, and the route of administrationutilized. Determination of a therapeutically effective amount is wellwithin the capability of those skilled in the art, especially in lightof the detailed disclosure provided herein.

A therapeutically effective amount of a compound of structural formula(I) required for use in therapy varies with the nature of the conditionbeing treated, the length of time that activity is desired, and the ageand the condition of the patient, and ultimately is determined by theattendant physician. Dosage amounts and intervals can be adjustedindividually to provide plasma levels of the DCN1 inhibitor that aresufficient to maintain the desired therapeutic effects. The desired doseconveniently can be administered in a single dose, or as multiple dosesadministered at appropriate intervals, for example as one, two, three,four or more subdoses per day. Multiple doses often are desired, orrequired. For example, a present DCN1 inhibitor can be administered at afrequency of: one dose per day for 2 days with rest for 5 days for 2weeks; one dose per day for 3 days with rest for 4 days for 3 weeks;weekly dosing for 2 weeks; weekly dosing for 4 weeks; or, any doseregimen determined to be appropriate for the circumstance.

A compound of structural formula (I) used in a method of the presentinvention can be administered in an amount of about 0.005 to about 500milligrams per dose, about 0.05 to about 250 milligrams per dose, orabout 0.5 to about 100 milligrams per dose. For example, a compound ofstructural formula (I) can be administered, per dose, in an amount ofabout 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300,350, 400, 450, or 500 milligrams, including all doses between 0.005 and500 milligrams.

The dosage of a composition containing a DCN1 inhibitor of structuralformula (I) or a composition containing the same, can be from about 1ng/kg to about 200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1mg/kg to about 50 mg/kg. The dosage of a composition can be at anydosage including, but not limited to, about 1 μg/kg. The dosage of acomposition may be at any dosage including, but not limited to, about 1μg/kg, 10 μg/kg, 25 μg/kg, 50 μg/kg, 75 μg/kg, 100 μg/kg, 125 μg/kg, 150μg/kg, 175 μg/kg, 200 μg/kg, 225 μg/kg, 250 μg/kg, 275 μg/kg, 300 μg/kg,325 μg/kg, 350 μg/kg, 375 μg/kg, 400 μg/kg, 425 μg/kg, 450 μg/kg, 475μg/kg, 500 μg/kg, 525 μg/kg, 550 μg/kg, 575 μg/kg, 600 μg/kg, 625 μg/kg,650 μg/kg, 675 μg/kg, 700 μg/kg, 725 μg/kg, 750 μg/kg, 775 μg/kg, 800μg/kg, 825 μg/kg, 850 μg/kg, 875 μg/kg, 900 μg/kg, 925 μg/kg, 950 μg/kg,975 μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, or 200mg/kg. The above dosages are exemplary of the average case, but therecan be individual instances in which higher or lower dosages aremerited, and such are within the scope of this invention. In practice,the physician determines the actual dosing regimen that is most suitablefor an individual patient, which can vary with the age, weight, andresponse of the particular patient.

In the treatment of a cancer, a compound of structural formula (I) canbe administered with a chemotherapeutic agent and/or radiation.

Embodiments of the present invention employ electromagnetic radiationof: gamma-radiation (10-20 to 10-13 m), X-ray radiation (10-12 to 10-9m), ultraviolet light (10 nm to 400 nm), visible light (400 nm to 700nm), infrared radiation (700 nm to 1 mm), and microwave radiation (1 mmto 30 cm).

Many cancer treatment protocols currently employ radiosensitizersactivated by electromagnetic radiation, e.g., X-rays. Examples ofX-ray-activated radiosensitizers include, but are not limited to,metronidazole, misonidazole, desmethylmisonidazole, pimonidazole,etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145,nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR),bromodeoxycytidine, fluorodeoxyuridine (FUdR), hydroxyurea, cis-platin,and therapeutically effective analogs and derivatives of the same.

Photodynamic therapy (PDT) of cancers employs visible light as theradiation activator of the sensitizing agent. Examples of photodynamicradiosensitizers include the following, but are not limited to:hematoporphyrin derivatives, PHOTOFRIN®, benzoporphyrin derivatives,NPe6, tin etioporphyrin (SnET2), pheoborbide-a, bacteriochlorophyll-a,naphthalocyanines, phthalocyanines, zinc phthalocyanine, andtherapeutically effective analogs and derivatives of the same.

Radiosensitizers can be administered in conjunction with atherapeutically effective amount of one or more compounds in addition toa present DCN1 inhibitor, such compounds including, but not limited to,compounds that promote the incorporation of radiosensitizers to thetarget cells, compounds that control the flow of therapeutics,nutrients, and/or oxygen to the target cells, chemotherapeutic agentsthat act on the tumor with or without additional radiation, or othertherapeutically effective compounds for treating cancer or otherdisease. Examples of additional therapeutic agents that can be used inconjunction with radiosensitizers include, but are not limited to,5-fluorouracil (5-FU), leucovorin, oxygen, carbogen, red celltransfusions, perfluorocarbons (e.g., FLUOSOLW®-DA), 2,3-DPG, BW12C,calcium channel blockers, pentoxifylline, antiangiogenesis compounds,hydralazine, and L-BSO.

The chemotherapeutic agent can be any pharmacological agent or compoundthat induces apoptosis. The pharmacological agent or compound can be,for example, a small organic molecule, peptide, polypeptide, nucleicacid, or antibody. Chemotherapeutic agents that can be used include, butare not limited to, alkylating agents, antimetabolites, hormones andantagonists thereof, natural products and their derivatives,radioisotopes, antibodies, as well as natural products, and combinationsthereof. For example, a DCN1 inhibitor of the present invention can beadministered with antibiotics, such as doxorubicin and otheranthracycline analogs, nitrogen mustards, such as cyclophosphamide,pyrimidine analogs such as 5-fluorouracil, cis-platin, hydroxyurea,taxol and its natural and synthetic derivatives, and the like. Asanother example, in the case of mixed tumors, such as adenocarcinoma ofthe breast, where the tumors include gonadotropin-dependent andgonadotropin-independent cells, the compound can be administered inconjunction with leuprolide or goserelin (synthetic peptide analogs ofLH-RH). Other antineoplastic protocols include the use of an inhibitorcompound with another treatment modality, e.g., surgery or radiation,also referred to herein as “adjunct anti-neoplastic modalities.”Additional chemotherapeutic agents useful in the invention includehormones and antagonists thereof, radioisotopes, antibodies, naturalproducts, and combinations thereof.

Examples of chemotherapeutic agents useful in a method of the presentinvention are listed in the following table.

TABLE 1 Alkylating agents Natural products Nitrogen mustards Antimitoticdrugs mechlorethamine Taxanes cyclophosphamide paclitaxel ifosfamideVinca alkaloids melphalan vinblastine (VLB) chlorambucil vincristineuracil mustard vinorelbine temozolomide vindesine NitrosoureasTaxotere ® (docetaxel) carmustine (BCNU) estramustine lomustine (CCNU)estramustine phosphate semustine (methyl-CCNU) Epipodophylotoxinschlormethine etoposide streptozocin teniposideEthylenimine/Methyl-melamine Antibiotics triethylenemelamine (TEM)actimomycin D triethylene thiophosphoramide daunomycin (rubidomycin)(thiotepa) doxorubicin (adriamycin) hexamethylmelaminemitoxantroneidarubicin (HMM, altretamine) bleomycin Alkyl sulfonatessplicamycin (mithramycin) busulfan mitromycin-C pipobroman dactinomycinTriazines aphidicolin dacarbazine (DTIC) epirubicin Antimetabolitesidarubicin Folic Acid analogs daunorubicin methotrexate mithramycintrimetrexate deoxy co-formycin pemetrexed Enzymes (Multi-targetedantifolate) L-asparaginase Pyrimidine analogs L-arginase 5-fluorouracilRadiosensitizers fluorodeoxyuridine metronidazole gemcitabinemisonidazole cytosine arabinoside desmethylmisonidazole (AraC,cytarabine) pimonidazole 5-azacytidine etanidazole2,2′-difluorodeoxy-cytidine nimorazole floxuridine RSU 1069 pentostatineEO9 Purine analogs RB 6145 6-mercaptopurine Nonsteroidal antiandrogens6-thioguanine SR4233 azathioprine flutamide 2′-deoxycoformycinnicotinamide (pentostatin) 5-bromodeozyuridineerythrohydroxynonyl-adenine 5-iododeoxyuridine (EHNA) fludarabinephosphate bromodeoxycytidine 2-chlorodeoxyadenosine Miscellaneous agents(cladribine, 2-CdA) Platinium coordination complexes Type ITopoisomerase Inhibitors cisplatin camptothecin carboplatin topotecanoxaliplatin irinotecan anthracenedione Biological response modifiersmitoxantrone G-CSF Substituted urea GM-CSF hydroxyurea DifferentiationAgents Methylhydrazine derivatives retinoic acid derivativesN-methylhydrazine (MIH) Hormones and antagonists procarbazineAdrenocorticosteroids/antagonists Adrenocortical suppressant prednisoneand equivalents mitotane (o,p′-DDD) dexamethasone ainoglutethimideainoglutethimide Cytokines Progestins interferon (α, β, γ)hydroxyprogesterone caproate interleukin-2 medroxyprogesterone acetatePhotosensitizers megestrol acetate hematoporphyrin derivatives EstrogensPHOTOFRIN ® diethylstilbestrol benzoporphyrin derivatives ethynylestradiol/equivalents Npe6 Antiestrogen tin etioporphyrin (SnET2)tamoxifen pheoboride-a Androgens bacteriochlorophyll-a testosteronepropionate naphthalocyanines fluoxymesterone/equivalents phthalocyaninesAntiandrogens zinc phthalocyanines flutamide Radiationgonadotropin-releasing X-ray hormone analogs ultraviolet lightleuprolide gamma radiation visible light infrared radiation microwaveradiation

Microtubule affecting agents interfere with cellular mitosis and arewell known in the art for their cytotoxic activity. Microtubuleaffecting agents useful in the invention include, but are not limitedto, allocolchicine (NSC 406042), halichondrin B (NSC 609395),colchicines (NSC 757), colchicines derivatives (e.g., NSC 33410),dolastatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC332598), paclitaxel (NSC 125973), TAXOL® derivatives (e.g., NSC 608832),thiocolchicine NSC 361792), trityl cysteine (NSC 83265), vinblastinesulfate (NSC 49842), vincristine sulfate (NSC 67574), natural andsynthetic epothilones including but not limited to epothilone A,eopthilone B, and discodermolide (see Service, (1996) Science, 274:2009)estramustine, nocodazole, MAP4, and the like. Examples of such agentsare also described in Bulinski (1997) J. Cell Sci. 110:3055 3064; Panda(1997) Proc. Natl. Acad. Sci. USA 94:10560-10564; Muhlradt (1997) CancerRes. 57:3344-3346; Nicolaou (1997) Nature 397:268-272; Vasquez (1997)Mol. Biol. Cell. 8:973-985; and Panda (1996) J. Biol. Chem.271:29807-29812.

Cytostatic agents that may be used include, but are not limited to,hormones and steroids (including synthetic analogs):17-α-ethinylestadiol, diethylstilbestrol, testosterone, prednisone,fluoxymesterone, dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyl-testosterone, prednisolone,triamcinolone, hlorotrianisene, hydroxyprogesterone, aminogluthimide,estramustine, medroxyprogesteroneacetate, leuprolide, flutamide,toremifene, and zoladex.

Other cytostatic agents are antiangiogenics, such as matrixmetalloproteinase inhibitors, and other VEGF inhibitors, such asanti-VEGF antibodies and small molecules such as ZD6474 and SU668.Anti-Her2 antibodies also may be utilized. An EGFR inhibitor is EKB-569(an irreversible inhibitor). Also included are antibody C225immunospecific for the EGFR and Src inhibitors.

Also suitable for use as a cytostatic agent is CASODEX® (bicalutamide,Astra Zeneca) which renders androgen-dependent carcinomasnon-proliferative. Yet another example of a cytostatic agent is theantiestrogen TAMOXIFEN® which inhibits the proliferation or growth ofestrogen dependent breast cancer. Inhibitors of the transduction ofcellular proliferative signals are cytostatic agents. Representativeexamples include epidermal growth factor inhibitors, Her-2 inhibitors,MEK-1 kinase inhibitors, MAPK kinase inhibitors, PI3 inhibitors, Srckinase inhibitors, and PDGF inhibitors.

The compounds of the present invention typically are administered inadmixture with a pharmaceutical carrier selected with regard to theintended route of administration and standard pharmaceutical practice.Pharmaceutical compositions for use in accordance with the presentinvention are formulated in a conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries that facilitate processing of compounds of structuralformula (I).

These pharmaceutical compositions can be manufactured, for example, byconventional mixing, dissolving, granulating, dragee-making,emulsifying, encapsulating, entrapping, or lyophilizing processes.Proper formulation is dependent upon the route of administration chosen.When a therapeutically effective amount of the compound of structuralformula (I) is administered orally, the composition typically is in theform of a tablet, capsule, powder, solution, or elixir. Whenadministered in tablet form, the composition additionally can contain asolid carrier, such as a gelatin or an adjuvant. The tablet, capsule,and powder contain about 0.01% to about 95%, and preferably from about1% to about 50%, of a compound of structural formula (I). Whenadministered in liquid form, a liquid carrier, such as water, petroleum,or oils of animal or plant origin, can be added. The liquid form of thecomposition can further contain physiological saline solution, dextroseor other saccharide solutions, or glycols. When administered in liquidform, the composition contains about 0.1% to about 90%, and preferablyabout 1% to about 50%, by weight, of a compound of structural formula(I).

When a therapeutically effective amount of a compound of structuralformula (I) is administered by intravenous, cutaneous, or subcutaneousinjection, the composition is in the form of a pyrogen-free,parenterally acceptable aqueous solution. The preparation of suchparenterally acceptable solutions, having due regard to pH, isotonicity,stability, and the like, is within the skill in the art. A preferredcomposition for intravenous, cutaneous, or subcutaneous injectiontypically contains, an isotonic vehicle.

Compounds of structural formula (I) can be readily combined withpharmaceutically acceptable carriers well-known in the art. Suchcarriers enable the active agents to be formulated as tablets, pills,dragees, capsules, liquids, gels, syrups, slurries, suspensions and thelike, for oral ingestion by a patient to be treated. Pharmaceuticalpreparations for oral use can be obtained by adding the compound ofstructural formula (I) to a solid excipient, optionally grinding theresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries, if desired, to obtain tablets or dragee cores.Suitable excipients include, for example, fillers and cellulosepreparations. If desired, disintegrating agents can be added.

A compound of structural formula (I) can be formulated for parenteraladministration by injection, e.g., by bolus injection or continuousinfusion. Formulations for injection can be presented in unit dosageform, e.g., in ampules or in multidose containers, with an addedpreservative. The compositions can take such forms as suspensions,solutions, or emulsions in oily or aqueous vehicles, and can containformulatory agents such as suspending, stabilizing, and/or dispersingagents.

Pharmaceutical compositions for parenteral administration includeaqueous solutions of the active agent in water-soluble form.Additionally, suspensions of a compound of structural formula (I) can beprepared as appropriate oily injection suspensions. Suitable lipophilicsolvents or vehicles include fatty oils or synthetic fatty acid esters.Aqueous injection suspensions can contain substances which increase theviscosity of the suspension. Optionally, the suspension also can containsuitable stabilizers or agents that increase the solubility of thecompounds and allow for the preparation of highly concentratedsolutions. Alternatively, a present composition can be in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

A compound of structural formula (I) also can be formulated in rectalcompositions, such as suppositories or retention enemas, e.g.,containing conventional suppository bases. In addition to theformulations described previously, the compound of structural formula(I) also can be formulated as a depot preparation. Such long-actingformulations can be administered by implantation (for example,subcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds of structural formula (I) can be formulatedwith suitable polymeric or hydrophobic materials (for example, as anemulsion in an acceptable oil) or ion exchange resins.

In particular, the compounds of structural formula (I) can beadministered orally, buccally, or sublingually in the form of tabletscontaining excipients, such as starch or lactose, or in capsules orovules, either alone or in admixture with excipients, or in the form ofelixirs or suspensions containing flavoring or coloring agents. Suchliquid preparations can be prepared with pharmaceutically acceptableadditives, such as suspending agents. The compounds of structuralformula (I) also can be injected parenterally, for example,intravenously, intramuscularly, subcutaneously, or intracoronarily. Forparenteral administration, the DCN1 inhibitors are best used in the formof a sterile aqueous solution which can contain other substances, forexample, salts or monosaccharides, such as mannitol or glucose, to makethe solution isotonic with blood.

As an additional embodiment, the present invention includes kits whichcomprise one or more compounds or compositions packaged in a manner thatfacilitates their use to practice methods of the invention. In onesimple embodiment, the kit includes a compound or composition describedherein as useful for practice of a method (e.g., a compositioncomprising a compound of structural formula (I) and an optional secondtherapeutic agent), packaged in a container, such as a sealed bottle orvessel, with a label affixed to the container or included in the kitthat describes use of the compound or composition to practice the methodof the invention. Preferably, the compound or composition is packaged ina unit dosage form. The kit further can include a device suitable foradministering the composition according to the intended route ofadministration.

In addition to its use in therapeutic medicine, compounds of structuralformula (I), and pharmaceutically acceptable salts thereof, also areuseful as pharmacological tools in the development and standardizationof in vitro and in vivo test systems for the evaluation of the effectsof inhibitors of DCN1 in laboratory animals, such as cats, dogs,rabbits, monkeys, rats, and mice, as part of the search for newtherapeutic agents.

In accordance with an important feature of the present invention,compounds of structural formula (I) were synthesized and evaluated asinhibitors for DCN1. For example, compounds of the present inventiontypically have a binding affinity (IC50) to DCN1 of less than 500 nM.

Compounds of structural formula (I) were prepared using the followingsynthetic procedures.

A. Synthesis of Intermediate Amino Acids

As shown in scheme 1, compounds 3 were afforded by transforming thecarboxylic acid of compound 1 to benzothiazoles. A reported method¹ wasemployed for form the benzothiazole ring.

Allyl(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-isopropylbenzo[d]thiazol-2-yl)propanoate(2a): To a solution of(S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(allyloxy)-4-oxobutanoicacid (1, 5 g, 12.6 mmol) in CH₂Cl₂ (300 mL) was added oxalyl chloride(3.3 mL, 38.0 mmol) and catalytic amount of DMF at 0° C. The reactionmixture was concentrated after being stirred for 0.5 h. The residue wassuspended in toluene (250 mL) and treated with2-amino-5-isopropylbenzenethiol (2.1 g, 12.6 mmol). The resultantmixture was stirred overnight at room temperature. The solution wasdiluted with EtOAc and washed with saturated sodium bicarbonate, 1.0 MHCl, brine and dried over sodium sulfate. The solvent was evaporated andthe crude product was purified by flash chromatography on silica gel toafford intermediate 2a (3.5 g, 53%). ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d,J=8.4 Hz, 1H), 7.86-7.75 (m, 2H), 7.72 (s, 1H), 7.65 (t, J=7.1 Hz, 2H),7.49-7.36 (m, 3H), 7.33-7.27 (m, 2H), 6.46 (d, J=8.5 Hz, 1H), 5.98-5.88(m, 1H), 5.36 (d, J=17.2 Hz, 1H), 5.25 (dd, J=10.4, 0.8 Hz, 1H), 5.02(dt, J=8.5, 5.3 Hz, 1H), 4.72 (d, J=4.9 Hz, 2H), 4.46 (d, J=7.3 Hz, 2H),4.30 (t, J=7.3 Hz, 1H), 3.75 (qd, J=15.7, 5.3 Hz, 2H), 3.08 (dt, J=13.7,6.9 Hz, 1H), 1.37 (d, J=6.9 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 170.46,165.13, 156.11, 151.53, 146.40, 143.98, 143.89, 141.35, 135.55, 131.60,127.75, 127.14, 125.38, 125.30, 122.69, 120.04, 118.86, 118.74, 67.36,66.42, 53.35, 47.19, 35.76, 34.30, 24.30. UPLC-MS (ESI-MS) m/z:calculated for C₃₁H₃₁N₂O₄S⁺ 527.20, found 527.26 [M+H]⁺.

Allyl(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-chlorobenzo[d]thiazol-2-yl)propanoate(2b): Intermediate 2b was prepared in 46% yield by a similar procedureas that for 2a. ¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, J=8.7 Hz, 1H), 7.84(d, J=1.4 Hz, 1H), 7.78 (d, J=7.3 Hz, 2H), 7.67-7.54 (m, 2H), 7.52-7.37(m, 3H), 7.36-7.22 (m, 2H), 6.12 (d, J=8.1 Hz, 1H), 5.95-5.82 (m, 1H),5.32 (d, J=17.3 Hz, 1H), 5.23 (d, J=10.3 Hz, 1H), 5.03-4.85 (m, 1H),4.68 (d, J=5.1 Hz, 2H), 4.43 (d, J=7.1 Hz, 2H), 4.27 (t, J=7.0 Hz, 1H),3.71 (qd, J=15.8, 4.9 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 170.16, 166.49,155.90, 151.56, 143.72, 141.31, 136.40, 131.32, 131.20, 127.74, 127.07,126.97, 125.15, 123.70, 121.17, 120.02, 119.05, 67.30, 66.52, 52.98,47.11, 35.79.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-isopropylbenzo[d]thiazol-2-yl)propanoicacid (3a): Phenylsilane (1.9 g, 17.1 mmol) was added to a solution of 2a(3.0 g, 5.7 mmol) and Tetrakis(triphenylphosphine)palladium(0) (658 mg,0.57 mmol) in DCM. The resultant solution was stirred 1 h before beingconcentrated. The residue was purified by flash chromatography on silicagel to afford 3a (2.24 g, 81%). ¹H NMR (400 MHz, DMSO) δ 8.01-7.82 (m,5H), 7.64 (dd, J=11.7, 7.6 Hz, 2H), 7.41-7.37 (m, 3H), 7.29-7.25 (m,1H), 7.23-7.13 (m, 1H), 4.57-4.51 (m, 1H), 4.30-4.16 (m, 3H), 3.60 (dd,J=15.1, 4.6 Hz, 1H), 3.44 (dd, J=15.0, 9.9 Hz, 1H), 3.03 (dt, J=13.7,6.8 Hz, 1H), 1.26 (d, J=6.9 Hz, 6H). ¹³C NMR (101 MHz, DMSO) δ 172.71,167.25, 156.39, 151.46, 146.13, 144.23, 144.14, 141.15, 135.65, 128.06,127.49, 125.71, 125.65, 125.51, 122.45, 120.55, 119.48, 66.18, 54.10,47.04, 35.53, 33.97, 24.55, 24.54. UPLC-MS (ESI-MS) m/z: calculated forC₂₈H₂₇N₂O₄S⁺ 487.17, found 487.19 [M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-chlorobenzo[d]thiazol-2-yl)propanoicacid (3b): Intermediate 3b was prepared from 2b in 79% yield by asimilar procedure as that for 3a. ¹H NMR (300 MHz, CD₃OD:CCl₃D=1:10) δ7.84 (d, J=8.7 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.72 (d, J=7.5 Hz, 2H),7.57-7.54 (m, 2H), 7.43-7.30 (m, 3H), 7.24 (t, J=7.4 Hz, 2H), 4.95-4.66(m, 1H), 4.45-4.25 (m, 2H), 4.19 (t, J=7.0 Hz, 1H), 3.67-3.64 (m, 2H).¹³C NMR (75 MHz, CD₃OD:CCl₃D=1:10) δ 172.19, 167.48, 156.13, 151.13,143.66, 141.24, 136.32, 131.19, 127.68, 127.02, 126.96, 125.06, 123.37,121.15, 119.93, 67.15, 52.92, 47.03, 35.67. UPLC-MS (ESI-MS) m/z:calculated for C₂₅H₂₀ClN₂O₄S⁺ 479.08, found 479.19 [M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chlorobenzo[d]thiazol-2-yl)propanoicacid (3c): Intermediate 3c was prepared from 1 in 41% yield in two stepsusing a similar procedure as that for 3a. ¹H NMR (400 MHz, DMSO) δ 13.04(br, 1H), 8.11 (d, J=8.6 Hz, 1H), 8.02 (d, J=1.9 Hz, 1H), 7.93 (d, J=8.6Hz, 1H), 7.88 (d, J=7.5 Hz, 2H), 7.67-7.94 (m, 2H), 7.48 (dd, J=8.6, 2.0Hz, 1H), 7.41-7.38 (m, 2H), 7.30-7.22 (m, 2H), 4.54 (td, J=9.5, 4.6 Hz,1H), 4.29-4.27 (m, 2H), 4.20 (t, J=6.8 Hz, 1H), 3.63 (dd, J=15.2, 4.5Hz, 1H), 3.47 (dd, J=15.1, 9.9 Hz, 1H). ¹³C NMR (101 MHz, DMSO) δ172.59, 170.94, 156.41, 153.89, 144.21, 144.15, 141.17, 134.25, 131.33,128.07, 127.48, 125.64, 125.57, 124.05, 122.28, 120.57, 66.15, 53.92,47.05, 35.62. UPLC-MS (ESI-MS) m/z: calculated for C₂₅H₂₀ClN₂O₄S⁺479.08, found 479.22[M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-fluorobenzo[d]thiazol-2-yl)propanoicacid (3d): Intermediate 3d was prepared from 1 in 36% yield in two stepsusing a similar procedure as that for 3a. ¹H NMR (400 MHz, DMSO), δ 13.0(br. 1H), 7.97-7.87 (m, 4H), 7.66-7.64 (m, 2H), 7.87 (d, J=7.5, 2H),7.48-7.22 (m, 6H), 4.54 (dt, J=4.0, 8.8, 1H), 4.28 (d, J=6.3, 2H), 4.20(t, J=6.8, 1H), 3.65 (dd, J=4.6, 15.1, 1H), 3.49 (dd, J=9.9, 15.1, 1H);¹³C NMR (75 MHz, CD3OD).

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluorobenzo[d]thiazol-2-yl)propanoicacid (3e): Intermediate 3e was prepared from 1 in 39% yield in two stepsusing a similar procedure as that for 3a: ¹H NMR (400 MHz, DMSO), δ 13.0(br. 1H), 8.12-8.09 (m, 1H), 7.94 (d, J=8.6, 1H), 7.87 (d, J=7.5, 2H),7.79 (dd, J=2.5, 9.9, 1H), 7.67-7.64 (m, 2H), 7.41-7.23 (m, 5H), 4.55(dt, J=4.0, 9.4, 1H), 4.29 (d, J=6.7, 2H), 4.20 (t, J=6.8, 1H), 3.63(dd, J=4.5, 15.1, 1H), 3.47 (dd, J=9.8, 15.1, 1H); ¹³C NMR (75 MHz,CD3OD).

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-fluorobenzo[d]thiazol-2-yl)propanoicacid (3f): Intermediate 3f was prepared from 1 in 32% yield in two stepsusing a similar procedure as that for 3a: ¹H NMR (400 MHz, DMSO), δ 13.0(br. 1H), 7.99-7.92 (m, 3H), 7.88 (d, J=7.5, 2H), 7.67-7.64 (m, 2H),7.42-7.34 (m, 3H), 7.30-7.23 (m, 2H), 4.54 (dt, J=4.4, 8.6, 1H), 4.28(d, J=7.0, 2H), 4.20 (t, J=6.8, 1H), 3.60 (dd, J=4.3, 15.1, 1H), 3.45(dd, J=9.8, 15.1, 1H); ¹³C NMR (75 MHz, CD3OD).

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(7-chlorobenzo[d]thiazol-2-yl)propanoicacid (3g): Intermediate 3g was prepared from 1 in 35% yield in two stepsusing a similar procedure as that for 3a. ESI-MS m/z: calculated forC₂₅H₂₀ClN₂O₄S⁺ 479.1, found 479.4 [M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-methylbenzo[d]thiazol-2-yl)propanoicacid (3h): Intermediate 3h was prepared from 1 in two steps using asimilar procedure as that for 3a. ESI-MS m/z: calculated forC₂₆H₂₃N₂O₄S+459.1, found 459.8 [M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-ethylbenzo[d]thiazol-2-yl)propanoicacid (3i): Intermediate 3i was prepared from 1 in two steps using asimilar procedure as that for 3a. ESI-MS m/z: calculated forC₂₇H₂₅N₂O₄S+ 473.2, found 473.5[M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-(1,1-dimethylethyl)benzo[d]thiazol-2-yl)propanoicacid (3j): Intermediate 3j was prepared from 1 in two steps using asimilar procedure as that for 3a. ESI-MS m/z: calculated forC₂₉H₂₉N₂O₄S+ 501.2, found 501.9 [M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-bromobenzo[d]thiazol-2-yl)propanoicacid (3k): Intermediate 3k was prepared from 1 in two steps using asimilar procedure as that for 3a. ESI-MS m/z: calculated forC₂₅H₂₀BrN₂O₄S⁺ 523.0, found 523.6 [M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-methylbenzo[d]thiazol-2-yl)propanoicacid (3s): Intermediate 3s was prepared from 1 in two steps using asimilar procedure as that for 3a. ESI-MS m/z: calculated forC₂₅H₁₈C₁₂N₂O₄S⁺ 512.0, found 512.5 [M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(benzo[d]oxazol-2-yl)propanoicacid (3l): To a solution of(S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(allyloxy)-4-oxobutanoicacid (1, 5 g, 12.6 mmol) in CH₂Cl₂ (300 mL) was added oxalyl chloride(3.3 mL, 38.0 mmol) and catalytic amount of DMF at 0° C. The reactionmixture was concentrated after being stirred for 0.5 h. The residue wassuspended in CH₂Cl₂ (250 mL) and treated with2-amino-5-isopropylbenzenethiol (2.1 g, 12.6 mmol) andN,N-Diisopropylethylamine (5 mL). The resulting mixture was stirred for3 h and treated with water. The separated organic phase was dried overNa₂SO₄ and concentrated to get 3l-1. Trifluoromethanesulfonic anhydride(3.2 ml, 18.9 mmol) was added slowly to a solution of triphenylphosphaneoxide (10.5 g, 37.8 mmol) in dry CH₂Cl₂ (250 mL) at 0° C. After themixture was stirred at 0° C. for 10 min, 3l-1 was then added at the sametemperature. The reaction was allowed to warm to room temperature andstirred for 5 h. The reaction mixture was quenched with 10% aqueousNaHCO₃ solution. The aqueous layer was extracted with CH₂Cl₂, and thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The crude product was purified by flash chromatography onsilica gel to afford 3l. ESI-MS m/z: calculated for C₂₅H₂₁N₂O₅ ⁺ 429.1,found 429.6.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-chlorobenzo[d]oxazol-2-yl)propanoicacid (3m): Intermediate 3m was prepared from 1 in two steps using asimilar procedure as that for 3l. ESI-MS m/z: calculated forC₂₅H₂₀ClN₂O₅ ⁺ 463.1, found 463.0 [M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chlorobenzo[d]oxazol-2-yl)propanoicacid (3n): Intermediate 3n was prepared from 1 in two steps using asimilar procedure as that for 3l. ESI-MS m/z: calculated forC₂₅H₂₀ClN₂O₅ ⁺ 463.1, found 463.2 [M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-methylbenzo[d]oxazol-2-yl)propanoicacid (3o): Intermediate 3o was prepared from 1 in two steps using asimilar procedure as that for 3l. ESI-MS m/z: calculated for C₂₆H₂₃N₂O₅⁺ 443.1, found 443.2 [M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-ethylbenzo[d]oxazol-2-yl)propanoicacid (3p): Intermediate 3p was prepared from 1 in two steps using asimilar procedure as that for 3l. ESI-MS m/z: calculated for C₂₇H₂₅N₂O₅⁺ 457.2, found 457.4 [M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-methoxybenzo[d]oxazol-2-yl)propanoicacid (3q): Intermediate 3q was prepared from 1 in two steps using asimilar procedure as that for 3l. ESI-MS m/z: calculated for C₂₆H₂₃N₂O₆⁺ 459.2, found 459.2 [M+H]⁺.

(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-trifluoromethylbenzo[d]oxazol-2-yl)propanoicacid (3r): Intermediate 3r was prepared from 1 in two steps using asimilar procedure as that for 3l. ESI-MS m/z: calculated forC₂₆H₂₀F₃N₂O₅ ⁺ 497.2, found 497.8 [M+H]⁺.

(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-(3-chlorophenyl)-4-methylthiazol-2-yl)propanoicacid (3s):(S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(allyloxy)-4-oxobutanoicacid (10.6 g, 27.3 mmol) was dissolved in dichloromethane then thesolution was added ammonium carbonate (4.3 g, 54.6 mmol), HBTU (16.6 g,43.68 mmol), HOBt (6.7 g, 43.68 mmol) and DIEA (14 ml, 81.9 mmol). Themixture was stirred at room temperature and monitored by TLC. After thereaction completed, the mixture was poured into saturated aqueous NaHCO₃and extract with DCM. The organic layer was washed with brine and thenevaporated for next reaction.

A solution of allyl (((9H-fluoren-9-yl)methoxy)carbonyl)-L-asparaginate(10 g, 28.6 mmol) and2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(11.56 g, 28.6 mmol) in THF (500 mL) was stirred at room temperature for18 h. The reaction mixture was then poured into saturated aqueous NaHCO3(300 ml). The mixture was extracted with ethyl acetate (2×100 ml). Theorganic fractions were combined, dried over Na2SO4, filtered, andconcentrated. The residue was purified by flash column chromatography.ESI-MS m/z: 411.7.

Allyl(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-amino-4-thioxobutanoate(700 mg, 1.7 mmol) and Na2CO3 (550 mg, 5.1 mmol) were dissolved in DMEunder ice bath and N2 atmosphere. 1-bromo-1-(3-chlorophenyl)propan-2-one(500 mg, 3.4 mmol) was slowly to the mixture, and allowed to stir in icebath for 10 mins, then slowly warm up to room temperature for 30 mins.Then TFAA (0.7 ml, 5.11 mmol) and 2,4,6-collidine (1.02 ml, 8.16 mmol)was added the white suspension mixture and stir for another 1 h in icebath. The solution was added saturated sodium bicarbonate aqueoussolution then extracted with ethyl acetate. The combined organic layerwas evaporated and purified by flash column chromatography. ESI-MS m/z:559.4.

Allyl(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-(3-chlorophenyl)-4-methylthiazol-2-yl)propanoate(100 mg, 0.178 mmol) was dissolved in dichloromethane in N₂ atmosphere.Tetrakis(triphenylphosphine)palladium(0) (31.6 mg, 0.026 mmol) andphenylsalen (0.09 ml, 0.715 mmol) was added subsequently to thesolution. The solution was allowed to stir for 1 h in room temperature.The organic solvent was evaporated and concentrated to give crude(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-(3-chlorophenyl)-4-methylthiazol-2-yl)propanoicacid (3s) which was used for next reaction without purification. ESI-MSm/z: 519.3.

Using the appropriate bromoketones, readily obtained by thermodynamicbromination of the corresponding methylketones, the above 5-substitutedthiazole amino acids (3t-3z) were also prepared using the aboveprocedure.

A2. Synthesis of Azidoamines 10.

tert-butyl (R)-(2-azido-1-cyclohexylethyl)carbamate, 10CH: 10CH was madeby referring a reported method.³ MsCl (710 mg, 6.2 mmol, 1.5 equiv.) wasadded dropwise to a solution of N-Boc-L-cyclohexylglycinol (1.00 g, 4.1mmol, 1 equiv.) and Et₃N (1.7 mL, 12.3 mmol, 3 equiv.) in CH₂Cl₂ (20 mL)at 0° C. The mixture was stirred 3 h at 0° C. and diluted with CH₂Cl₂.The mixture was washed with sat. aq NaHCO₃ (2×20 mL), IM HCl, and brine.The organic layer was dried (Na₂SO₄) and the solvent was removed invacuo. The residue was dissolved in DMF and NaN₃ (802 mg, 12.3 mmol, 3equiv.) was added. This reaction mixture was stirred at 60° C. forovernight and cooled to room temperature. EtOAc and H₂O were added tothis mixture and the aqueous layer was extracted with EtOAc. The organiclayer was washed with H₂O and brine. The organic layer was dried(Na₂SO₄) and the solvent was removed under vacuum. The crude product waspurified by flash chromatography this gave 10CH (617 mg, 56% over twosteps). ¹H NMR (400 MHz, CDCl₃) δ 4.60 (d, J=8.6 Hz, 1H), 3.63-3.29 (m,3H), 1.79-1.65 (m, 5H), 1.54-1.36 (m, 11H), 1.33-0.86 (m, 6H). ¹³C NMR(101 MHz, CDCl₃) δ 155.57, 79.48, 54.82, 52.72, 39.31, 29.77, 28.86,28.36, 28.29, 26.16, 25.97, 25.96. UPLC-MS (ESI-MS) m/z: calculated forC₁₃H₂₅N₄O₂ ⁺ 269.20, found [M+H]⁺.

Other 2-azidoethylamines, 10 Il, 10CP, 10CHM 10Bn and 10No were made byanalogous methods.

B. Synthesis of Dipeptide Intermediates

(S)-2-amino-N-((2S,3S)-1-azido-3-methylpentan-2-yl)-3-(6-isopropylbenzo[d]thiazol-2-yl)propanamide,(4aIl): To a solution of 3a (2.0 g, 4.1 mmol, 1 equiv.), HBTU (2.3 g,6.2 mmol, 1.5 equiv.) and DIEA (2.1 mL, 12.3 mmol, 3 equiv.) in DMF (20mL) was added (2S,3S)-1-azido-3-methylpentan-2-amine hydrochloride 10Il(0.8 g, 4.5 mmol, 1.1 equiv.) and the resultant mixture was stirred atroom temperature for 1 h. The solution was diluted with EtOAc and washedwith H₂O, saturated sodium bicarbonate, 1.0 M HCl, brine and dried oversodium sulfate. After removal of the solvent under vacuum, the residuewas treated with 3 mL diethylamine in Actonitrile (27 mL) for 1 h. Thereaction mixture was evaporated and the residue was purified by flashchromatography on silica gel to afford 4aIl (1.2 g 77%). ¹H NMR (400MHz, MeOD) δ 7.94 (d, J=8.5 Hz, 1H), 7.84 (d, J=1.7 Hz, 1H), 7.44 (dd,J=8.5, 1.7 Hz, 1H), 4.57 (dd, J=7.8, 5.2 Hz, 1H), 3.87 (td, J=7.3, 3.8Hz, 1H), 3.77 (dd, J=16.6, 5.2 Hz, 1H), 3.68 (dd, J=16.6, 7.8 Hz, 1H),3.47 (dd, J=12.8, 3.9 Hz, 1H), 3.41-3.35 (m, 1H), 3.06 (dq, J=13.6, 6.8Hz, 1H), 1.70-1.60 (m, 1H), 1.58-1.50 (m, 1H), 1.32 (d, J=6.9 Hz, 6H),1.24-1.12 (m, 1H), 0.96-0.91 (m, 6H). ¹³C NMR (101 MHz, MeOD) δ 167.35,164.24, 151.02, 146.98, 135.29, 125.36, 122.10, 118.60, 53.74, 52.01,36.06, 34.11, 34.05, 24.98, 23.15, 14.16, 10.11. UPLC-MS (ESI-MS) m/z:calculated for C₁₉H₂₉N₆OS⁺ 389.21, found 389.36[M+H]⁺.

(S)-2-acetamido-N-((2S,3S)-1-azido-3-methylpentan-2-yl)-3-(6-isopropylbenzo[d]thiazol-2-yl)propanamide,(5aIlAc): Acetic anhydride (46 mg, 0.45 mmoL, 2 equiv.) was added to asolution of 4aIl (87 mg, 0.22 mmoL, 1 equiv.) and DIEA (156 μL, 0.89mmol, 4 equiv.) in DCM (10 mL). The resulting reaction mixture wasstirred for half an hour and then was evaporated. The residue waspurified by flash chromatography on silica gel to afford compounds(5aIlAc): (89 mg, 92% yields). ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J=8.5Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.59 (d, J=9.1 Hz, 1H), 7.47-7.36 (m,2H), 5.06 (q, J=6.4 Hz, 1H), 4.02-3.82 (m, 1H), 3.64 (d, J=6.3 Hz, 2H),3.37 (qd, J=12.6, 5.3 Hz, 2H), 3.08 (dt, J=13.8, 6.9 Hz, 1H), 2.08 (s,3H), 1.65-1.58 (m, 1H), 1.51-1.39 (m, 1H), 1.33 (d, J=6.9 Hz, 6H),1.21-1.03 (m, 1H), 0.92 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.4 Hz, 3H). ¹³CNMR (101 MHz, CDCl₃) δ 171.12, 169.86, 168.43, 148.60, 147.43, 134.34,126.28, 121.25, 118.98, 53.54, 52.41, 52.37, 36.15, 35.62, 34.29, 25.06,24.10, 22.97, 15.39, 11.19. UPLC-MS (ESI-MS) m/z: calculated forC₂₁H₃₁N₆O₂S⁺ 431.22, found 431.36[M+H]⁺.

(S)-2-acetamido-N-((2S,3S)-1-amino-3-methylpentan-2-yl)-3-(6-isopropylbenzo[d]thiazol-2-yl)propanamide(6aIlAc): To a solution of compound 5aIlAc (45 mg, 0.11 mmol) in MeOH(10 mL) was added 10% Pd—C (20 mg). The solution was stirred under 1 atmof H₂ at room temperature for 3 hours before filtering through celiteand being concentrated. The resulting amine was purified by HPLC toafford 6aIlAc (38 mg, 91%). ¹H NMR (400 MHz, MeOD) δ 7.92-7.77 (m, 2H),7.49-7.36 (m, 1H), 4.87-4.85 (m, 1H), 4.01-3.96 (m, 1H), 3.69 (dd,J=15.2, 5.9 Hz, 1H), 3.55 (dd, J=15.2, 6.9 Hz, 1H), 3.30-3.19 (m, 1H),3.08 (dt, J=13.8, 6.9 Hz, 1H), 2.97 (dd, J=12.6, 11.3 Hz, 1H), 2.03 (s,3H), 1.68-1.54 (m, 1H), 1.48-1.41 (m, 1H), 1.33 (d, J=6.9 Hz, 6H),1.21-1.06 (m, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.86 (t, J=7.4 Hz, 3H). ¹³CNMR (101 MHz, MeOD) δ 172.45, 171.81, 167.06, 150.90, 146.80, 135.18,125.31, 121.29, 118.67, 53.09, 52.09, 41.76, 36.51, 34.60, 34.08, 24.77,23.14, 21.18, 14.22, 9.75. UPLC-MS (ESI-MS) m/z: calculated forC₂₁H₃₃N₄O₂S⁺ 405.23, found 405.25[M+H]⁺.

(S)—N-((2S,3S)-1-azido-3-methylpentan-2-yl)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamide,5aIlPr: Propionic anhydride (58 mg, 0.45 mmoL, 2 equiv.) was added to asolution of 4aIl (87 mg, 0.22 mmoL, 1 equiv.) and DIEA (156 μL, 0.89mmol, 4 equiv.) in DCM (10 mL). The resulting reaction mixture wasstirred for half an hour and then was evaporated. The residue waspurified by flash chromatography on silica gel to afford compound 5aIlPr(86 mg, 89% yields). ¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J=8.5 Hz, 1H),7.73 (d, J=1.0 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.50 (d, J=7.0 Hz, 1H),7.45 (dd, J=8.4, 1.5 Hz, 1H), 5.08 (dd, J=12.7, 6.8 Hz, 1H), 4.00-3.88(m, 1H), 3.75 (dd, J=15.3, 5.3 Hz, 1H), 3.63 (dd, J=15.3, 7.2 Hz, 1H),3.39 (qd, J=12.6, 5.4 Hz, 2H), 3.08 (dt, J=13.8, 6.9 Hz, 1H), 2.31 (q,J=7.6 Hz, 2H), 1.68-1.56 (m, 1H), 1.48-1.42 (m, 1H), 1.33 (d, J=6.9 Hz,6H), 1.20-1.05 (m, 4H), 0.92 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.4 Hz, 3H).¹³C NMR (101 MHz, CDCl₃) δ 175.27, 169.85, 169.08, 147.86, 147.47,133.89, 126.67, 120.89, 119.04, 53.65, 52.49, 52.36, 36.20, 35.35,34.30, 29.42, 25.07, 24.05, 24.04, 15.32, 11.17, 9.61. UPLC-MS (ESI-MS)m/z: calculated for C₂₂H₃₃N₆O₂S⁺ 445.24, found 445.37[M+H]⁺.

(S)—N-((2S,3S)-1-amino-3-methylpentan-2-yl)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamide(6aIlPr): To a solution of compound 5aIlPr (52 mg, 0.12 mmol) in MeOH(10 mL) was added 10% Pd—C (20 mg). The solution was stirred under 1 atmof H₂ at room temperature for 3 hours before filtering through celiteand being concentrated. The resulting amine was purified by HPLC toafford 6aIlPr (36 mg, 86%). ¹H NMR (400 MHz, MeOD) δ 7.90-7.80 (m, 2H),7.43 (dd, J=8.5, 1.7 Hz, 1H), 4.91-4.89 (m, 1H), 4.09-3.92 (m, 1H), 3.69(dd, J=15.2, 5.9 Hz, 1H), 3.55 (dd, J=15.2, 7.0 Hz, 1H), 3.29-3.20 (m,1H), 3.08 (dt, J=13.8, 6.9 Hz, 1H), 3.02-2.93 (m, 1H), 2.30 (q, J=7.6Hz, 2H), 1.67-1.56 (m, 1H), 1.48-1.42 (m, 1H), 1.33 (d, J=6.9 Hz, 6H),1.20-1.07 (m, 4H), 0.95 (d, J=6.8 Hz, 3H), 0.86 (t, J=7.4 Hz, 3H). ¹³CNMR (101 MHz, MeOD) δ 176.05, 171.86, 167.09, 150.90, 146.78, 135.16,125.30, 121.28, 118.66, 52.92, 52.07, 41.77, 36.54, 34.55, 34.07, 28.54,24.74, 23.14, 14.24, 9.76, 8.71. UPLC-MS (ESI-MS) m/z: calculated forC₂₂H₃₅N₄O₂S⁺ 419.25, found 419.29 [M+H]⁺.

(S)—N-((2S,3S)-1-amino-3-methylpentan-2-yl)-2-formamido-3-(6-isopropylbenzo[d]thiazol-2-yl)propanamide(5aIlFo): 4aIl (100 mg, 0.26 mmol) was dissolved in a mixture of DIEA (1mL) and Ethyl formate (5 mL) and the resulting reaction mixture was leftstirring for 3 days. The solvents were removed in vacuo and the residuewas dissolved in MeOH (10 ml). Then 10% Pd—C (20 mg) was added and theresulting reaction mixture was stirred under 1 atm of H₂ at roomtemperature for 3 hours before filtering through celite and beingconcentrated. The resulting amine was purified by HPLC to afford 5aIlFo(58 mg, 58%). ¹H NMR (400 MHz, MeOD) δ 8.18 (d, J=0.7 Hz, 1H), 7.87-7.81(m, 2H), 7.43 (dd, J=8.5, 1.7 Hz, 1H), 4.99 (t, J=5.6 Hz, 1H), 4.04-3.98(m, 1H), 3.69 (dd, J=15.3, 5.8 Hz, 1H), 3.63 (dd, J=15.3, 6.1 Hz, 1H),3.27 (dd, J=12.9, 2.4 Hz, 1H), 3.08 (dt, J=13.8, 6.9 Hz, 1H), 2.98 (dd,J=12.9, 11.1 Hz, 1H), 1.68-1.55 (m, 1H), 1.48-1.42 (m, 1H), 1.33 (d,J=6.9 Hz, 6H), 1.21-1.08 (m, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.85 (t, J=7.4Hz, 3H). ¹³C NMR (101 MHz, MeOD) δ 171.17, 166.62, 162.68, 150.95,146.81, 135.20, 125.30, 121.29, 118.67, 52.15, 52.06, 51.53, 41.84,36.56, 34.73, 34.07, 24.76, 23.13, 14.20, 9.73. UPLC-MS (ESI-MS) m/z:calculated for C₂₀H₃₁N₄O₂S⁺ 391.22, found 391.22 [M+H]⁺.

(S)—N-((2S,3S)-1-amino-3-methylpentan-2-yl)-2-isobutyramido-3-(6-isopropylbenzo[d]thiazol-2-yl)propanamide6aIlIB: 6aIB was prepared from 4aIl in 72% yield over two steps by asimilar procedure as that for compound 6aIlAc. ¹H NMR (400 MHz, MeOD) δ8.33 (d, J=7.3 Hz, 1H), 7.99 (d, J=8.9 Hz, 1H), 7.85-7.83 (m, 2H), 7.43(dd, J=8.6, 1.6 Hz, 1H), 4.91-4.88 (m, 1H), 4.09-3.90 (m, 1H), 3.69 (dd,J=15.2, 5.9 Hz, 1H), 3.55 (dd, J=15.2, 7.1 Hz, 1H), 3.26 (dd, J=13.4,3.1 Hz, 1H), 3.08 (dt, J=13.8, 6.9 Hz, 1H), 3.02-2.93 (m, 1H), 2.53 (dt,J=13.7, 6.9 Hz, 1H), 1.68-1.57 (m, 1H), 1.50-1.42 (m, 1H), 1.33 (d,J=6.9 Hz, 6H), 1.23-1.04 (m, 7H), 0.95 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.4Hz, 3H). ¹³C NMR (101 MHz, MeOD) δ 179.04, 171.85, 167.11, 150.91,146.78, 135.14, 125.30, 121.24, 118.67, 52.71, 52.02, 41.85, 36.59,34.59, 34.45, 34.07, 24.69, 23.13, 18.48, 18.17, 14.25, 9.78. UPLC-MS(ESI-MS) m/z: calculated for C₂₃H₃7N₄O₂S⁺ 433.26, found 433.29 [M+H]⁺.

N—((S)-1-(((2S,3S)-1-amino-3-methylpentan-2-yl)amino)-3-(6-isopropylbenzo[d]thiazol-2-yl)-1-oxopropan-2-yl)butyramide6aIlBu: 6aIlBu was prepared from 4aIl in 70% yield over two steps by asimilar procedure as that for compound 6aIlAc. ¹H NMR (400 MHz, MeOD) δ7.91-7.75 (m, 2H), 7.43 (dd, J=8.6, 1.6 Hz, 1H), 4.91-4.88 (m, 1H),4.02-3.96 (m, 1H), 3.69 (dd, J=15.2, 5.9 Hz, 1H), 3.54 (dd, J=15.2, 7.2Hz, 1H), 3.25 (dd, J=13.1, 3.1 Hz, 1H), 3.08 (dt, J=13.8, 6.9 Hz, 1H),2.98 (dd, J=12.8, 11.1 Hz, 1H), 2.35-2.18 (m, 2H), 1.71-1.55 (m, 3H),1.49-1.41 (m, 1H), 1.33 (d, J=6.9 Hz, 6H), 1.19-1.12 (m, 1H), 0.96-0.85(m, 9H). ¹³C NMR (101 MHz, MeOD) δ 175.14, 171.86, 167.08, 150.93,146.77, 135.17, 125.29, 121.28, 118.66, 52.90, 52.06, 41.78, 37.32,36.56, 34.61, 34.07, 24.74, 23.14, 18.76, 14.23, 12.56, 9.78. UPLC-MS(ESI-MS) m/z: calculated for C₂₃H₃7N₄O₂S⁺ 433.26, found 433.29 [M+H]⁺.

(S)—N-((2S,3S)-1-amino-3-methylpentan-2-yl)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-(3-methylureido)propanamide6aIlIC: Methyl isocyanate (18 mg, 0.31 mmol, 2 equiv.) was added to asolution of 4aIl (60 mg, 0.15 mmol, 1 equiv.) and DIEA (54 μL, 0.31mmol, 2 equiv.) in CH₂Cl₂ (5 mL) and the resulting solution was stirredat room temperature for overnight. The reaction mixture was concentratedand the residue was dissolved in MeOH (10 ml). Then 10% Pd—C (20 mg) wasadded and the resulting reaction mixture was stirred under 1 atm of H₂at room temperature for 3 hours before filtering through celite andbeing concentrated. The resulting amine was purified by HPLC to afford6aIlIC (58 mg, 74%). 1H NMR (400 MHz, MeOD) δ 7.85 (d, J=8.5 Hz, 1H),7.83 (d, J=1.7 Hz, 1H), 7.42 (dd, J=8.5, 1.7 Hz, 1H), 4.74 (t, J=5.8 Hz,1H), 3.99-3.94 (m, 1H), 3.61 (d, J=5.8 Hz, 2H), 3.24 (dd, J=12.9, 3.0Hz, 1H), 3.07 (dt, J=13.8, 6.9 Hz, 1H), 2.98 (dd, J=12.8, 11.3 Hz, 1H),2.74 (s, 3H), 1.58 (dtd, J=8.8, 7.3, 3.7 Hz, 1H), 1.44-1.35 (m, 1H),1.32 (d, J=6.9 Hz, 6H), 1.12-1.04 (m, 1H), 0.91 (d, J=6.8 Hz, 3H), 0.79(t, J=7.4 Hz, 3H). ¹³C NMR (101 MHz, MeOD) δ 172.94, 167.09, 159.77,150.97, 146.68, 135.23, 125.18, 121.40, 118.59, 53.78, 52.00, 41.73,36.52, 35.24, 34.07, 25.54, 24.79, 23.15, 14.24, 9.70. UPLC-MS (ESI-MS)m/z: calculated for C₂₁H₃₄N₅O₂S⁺ 420.24, found 419.29 [M+H]⁺.

(S)—N—((S)-2-azido-1-cyclohexylethyl)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamide,5aCHPr: Compound 5aCHPr was prepared from 3a and 10CH in 65% yield inthree steps by a similar procedure as that for compound 5aIlPr. ¹H NMR(400 MHz, CDCl₃) δ 7.84 (d, J=8.4 Hz, 1H), 7.69 (d, J=1.7 Hz, 1H), 7.50(d, J=9.1 Hz, 1H), 7.39 (d, J=7.1 Hz, 1H), 7.34 (dd, J=8.5, 1.7 Hz, 1H),5.04 (td, J=7.0, 4.8 Hz, 1H), 3.91-3.76 (m, 1H), 3.66 (dd, J=15.9, 4.7Hz, 1H), 3.43 (dd, J=15.9, 7.0 Hz, 1H), 3.35 (dd, J=5.0, 1.1 Hz, 2H),3.04 (dt, J=13.8, 6.9 Hz, 1H), 2.32 (q, J=7.6 Hz, 2H), 1.70-1.60 (dd,J=28.1, 15.3 Hz, 6H), 1.52-1.41 (m, 1H), 1.32-0.87 (m, 14H). ¹³C NMR(101 MHz, CDCl₃) δ 174.11, 170.30, 167.09, 150.97, 146.46, 135.25,125.39, 121.98, 118.79, 53.54, 52.31, 51.92, 38.95, 35.50, 34.24, 29.69,29.65, 28.51, 26.09, 25.91, 25.85, 24.18, 9.68. UPLC-MS (ESI-MS) m/z:calculated for C₂₄H₃₅N₆O₂S⁺ 471.25, found 471.27 [M+H]⁺.

(S)—N—((S)-2-amino-1-cyclohexylethyl)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamide:Compound 6aCHPr was prepared from 6aCHPr in 88% yield by a similarprocedure as that for 6aIlPr. ¹H NMR (400 MHz, MeOD) δ 7.99 (d, J=8.9Hz, 1H), 7.86-7.84 (m, 2H), 7.43 (d, J=8.5 Hz, 1H), 4.87-4.84 (m, 1H),3.94-3.90 (m, 1H), 3.68 (dd, J=15.3, 5.8 Hz, 1H), 3.56 (dd, J=15.2, 6.9Hz, 1H), 3.29-3.20 (m, 1H), 3.12-2.91 (m, 2H), 2.31 (q, J=7.6 Hz, 2H),1.75-1.63 (m, 5H), 1.54-1.46 (m, 1H), 1.36-0.90 (m, 14H). ¹³C NMR (101MHz, MeOD) δ 176.08, 171.86, 167.03, 150.94, 146.76, 135.15, 125.30,121.33, 118.65, 52.99, 52.48, 41.73, 39.59, 34.51, 34.08, 29.39, 28.57,28.25, 25.70, 25.50, 25.43, 23.14, 8.70. UPLC-MS (ESI-MS) m/z:calculated for C₂₄H₃₇N₄O₂S⁺ 445.26, found 445.27 [M+H]⁺.

(S)—N—((S)-2-amino-1-cyclopentylethyl)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamide6bCPPr: Compound 6bCPPr was prepared from 3b and 10CP by a similarprocedure as that for 6aIlPr. MS found: 423.3.

(S)—N—((S)-2-amino-1-cyclohexylethyl)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamide6bCHPr: Compound 6bCHPr was prepared from 3b and 10CH by a similarprocedure as that for 6aIlPr. ¹H NMR (400 MHz, MeOD) δ 8.02 (d, J=1.9Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.51 (dd, J=8.7, 2.1 Hz, 1H), 4.94-4.90(m, 1H), 3.95-3.90 (m, 1H), 3.71 (dd, J=15.4, 5.6 Hz, 1H), 3.57 (dd,J=15.4, 7.5 Hz, 1H), 3.24 (dd, J=13.0, 3.2 Hz, 1H), 3.05-2.93 (m, 1H),2.30 (q, J=7.6 Hz, 2H), 1.82-1.60 (m, 5H), 1.58-1.45 (m, 1H), 1.37-0.84(m, 8H). ¹³C NMR (101 MHz, MeOD) δ 176.15, 171.83, 168.87, 151.32,136.44, 130.95, 126.73, 122.77, 121.21, 52.90, 52.51, 41.57, 39.61,34.53, 29.40, 28.56, 28.24, 25.73, 25.51, 25.46, 8.71.

(S)—N—((S)-3-amino-1-cyclohexylprop-2-yl)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamide6bCHMPr: Compound 6bCHMPr was prepared from 3b and 10CHM by a similarprocedure as that for 6aIlPr. MS found: 451.5

((S)—N—((S)-3-amino-1-phenylprop-2-yl)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamide6bBnPr: Compound 6bBnPr was prepared from 3b and 10Bn by a similarprocedure as that for 6aIlPr. ¹H NMR (400 MHz, MeOD) δ 8.02 (d, J=2.0Hz, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.51 (dd, J=8.7, 2.1 Hz, 1H), 7.38-7.14(m, 5H), 4.84-4.82 (m, 1H), 4.46-4.32 (m, 1H), 3.59 (dd, J=15.4, 5.3 Hz,1H), 3.43 (dd, J=15.4, 8.1 Hz, 1H), 3.17 (dd, J=13.0, 3.8 Hz, 1H), 3.08(dd, J=12.9, 10.2 Hz, 1H), 2.98-2.79 (m, 2H), 2.24 (q, J=7.6 Hz, 2H),1.07 (t, J=7.6 Hz, 3H). ¹³C NMR (101 MHz, MeOD) δ 176.05 (s), 171.66(s), 168.80 (s), 151.27 (s), 136.79 (s), 136.46 (s), 130.93 (s), 128.79(s), 128.31 (s), 126.65 (d, J=13.1 Hz), 122.76 (s), 121.21 (s), 52.76(s), 49.42 (s), 42.95 (s), 37.43 (s), 34.72 (s), 28.50 (s), 8.59 (s).

(S)—N-(1-aminoeth-2-yl)-2-isobutyramido-3-(6-isopropylbenzo[d]thiazol-2-yl)propanamide6aNoIB: Compound 6aNoIB was prepared from 3a and 10No by a similarprocedure as that for 6aIlPr.

1H NMR (400 MHz, MeOD) δ 7.85 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 7.42 (d,J=8.5 Hz, 1H), 4.84-4.77 (m, 1H), 3.66 (dd, J=15.0, 5.3 Hz, 1H), 3.51(dd, J=13.8, 8.0 Hz, 3H), 3.17-2.99 (m, 3H), 2.52 (dt, J=13.7, 6.8 Hz,1H), 1.40-1.27 (m, 6H), 1.16-0.99 (m, 6H).

(S)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamide,6aBnPr. Compound 6aBnPr was prepared from 3a and 10Bn in 53% yield overfour steps by a similar procedure as that for compound 6aIlAc. ¹H NMR(400 MHz, MeOD) δ 7.86-7.80 (m, 2H), 7.42 (dd, J=8.5, 1.6 Hz, 1H),7.33-7.18 (m, 5H), 4.81 (dd, J=7.6, 5.5 Hz, 1H), 4.47-4.32 (m, 1H), 3.58(dd, J=15.2, 5.5 Hz, 1H), 3.42 (dd, J=15.2, 7.6 Hz, 1H), 3.18 (dd,J=13.0, 3.6 Hz, 1H), 3.10-3.04 (m, 2H), 2.93-2.84 (m, 2H), 2.24 (q,J=7.6 Hz, 2H), 1.32 (d, J=6.9 Hz, 6H), 1.08 (t, J=7.6 Hz, 3H). ¹³C NMR(101 MHz, MeOD) δ 175.96, 171.68, 167.04, 150.86, 146.74, 136.78,135.18, 128.77, 128.31, 126.58, 125.27, 121.31, 118.64, 52.86, 49.38,43.08, 37.43, 34.73, 34.07, 28.49, 23.14, 8.60. UPLC-MS (ESI-MS) m/z:calculated for C₂₅H₃₃N₄O₂S⁺ 453.23, found 453.24 [M+H]⁺.

(S)—N-(1-aminoeth-2-yl)-2-isobutyramido-3-(6-isopropylbenzo[d]thiazol-2-yl)propanamide6aNoCPR: Compound 6aNoCPR was prepared from 3a and 10No by a similarprocedure as that for 6aIlPr. ¹H NMR (400 MHz, MeOD) δ 8.41 (t, J=5.5Hz, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 7.42 (d, J=8.5 Hz, 1H),4.82 (dd, J=7.8, 5.8 Hz, 1H), 3.66 (dd, J=15.1, 5.8 Hz, 1H), 3.55-3.47(m, 3H), 3.17-2.97 (m, 3H), 1.80-1.59 (m, 1H), 1.33 (d, J=6.9 Hz, 6H),0.95-0.73 (m, 4H).

(S)—N-(2-aminoethyl)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamide(6aNoPr): To a solution of the 3a (120 mg, 0.25 mmol, 1 equiv.), HBTU(140 mg, 0.37 mmol, 1.5 equiv.) and DIEA (129 μL, 0.74 mmol, 3 equiv.)in DMF (5 mL) was added tert-butyl (2-aminoethyl)carbamate (43 mg, 0.27mmol, 1.1 equiv.) and the resultant mixture was stirred at roomtemperature for 1 h. The solution was diluted with EtOAc and washed withH₂O, saturated sodium bicarbonate, 1.0 M HCl, brine and dried oversodium sulfate. After removal of the solvent under vacuum, the residuewas treated with 1 mL diethylamine in Acetonitrile (9 mL) for 1 h. Thereaction mixture was evaporated and dissolved in DCM (5 mL). Thissolution was treated with propionic anhydride (64 mg, 0.49 mmoL, 2equiv.) and DIEA (171 μL, 0.99 mmol, 4 equiv.). The resulting reactionmixture was stirred for half an hour and then was evaporated. Theresidue was treated with TFA (1 ml) in DCM (5 mL) and stirred for 5 h.This reaction mixture was concentrated and purified by HPLC to afford6aNoPr (54 mg, 61%). ¹H NMR (400 MHz, MeOD) δ 7.86 (d, J=8.5 Hz, 1H),7.82 (d, J=1.7 Hz, 1H), 7.42 (dd, J=8.5, 1.7 Hz, 1H), 4.83 (dd, J=8.2,5.5 Hz, 1H), 3.67 (dd, J=15.1, 5.5 Hz, 1H), 3.56-3.43 (m, 3H), 3.10-3.03(m, 3H), 2.28 (q, J=7.6 Hz, 2H), 1.32 (d, J=6.9 Hz, 6H), 1.09 (t, J=7.6Hz, 3H). ¹³C NMR (101 MHz, MeOD) δ 176.04, 172.38, 166.94, 150.80,146.73, 135.22, 125.26, 121.46, 118.60, 53.15, 39.46, 36.83, 34.93,34.07, 28.50, 23.14, 8.56. UPLC-MS (ESI-MS) m/z: calculated forC₁₈H₂₇N₄O₂S+363.18, found 363.18 [M+H]⁺.

(S)—N—((S)-1-aminopropan-2-yl)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamide6aMePr: 6aMePr was prepared from 3a in 57% yield over four steps by asimilar procedure as that for compound 6aNoPr ¹H NMR (400 MHz, MeOD) δ7.86-7.83 (m, 2H), 7.42 (dd, J=8.5, 1.7 Hz, 1H), 4.84 (dd, J=7.1, 5.8Hz, 1H), 4.31-4.15 (m, 1H), 3.69 (dd, J=15.0, 5.8 Hz, 1H), 3.51 (dd,J=15.0, 7.2 Hz, 1H), 3.17-2.91 (m, 3H), 2.28 (q, J=7.6 Hz, 2H), 1.32 (d,J=6.9 Hz, 6H), 1.25 (d, J=6.9 Hz, 3H), 1.10 (t, J=7.6 Hz, 3H). ¹³C NMR(101 MHz, MeOD) δ 175.90, 171.51, 166.97, 150.86, 146.75, 135.21,125.29, 121.29, 118.65, 52.91, 44.65, 43.71, 35.02, 34.07, 28.52, 23.14,16.39, 8.65. UPLC-MS (ESI-MS) m/z: calculated for C₁₉H₂₉N₄O₂S⁺ 377.20,found 377.23 [M+H]⁺.

(S)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamide6aBnPr: 6aBnPr was prepared from 3a in 53% yield over four steps by asimilar procedure as that for 6aNoPr. ¹H NMR (400 MHz, MeOD) δ 7.86-7.80(m, 2H), 7.42 (dd, J=8.5, 1.6 Hz, 1H), 7.33-7.18 (m, 5H), 4.81 (dd,J=7.6, 5.5 Hz, 1H), 4.47-4.32 (m, 1H), 3.58 (dd, J=15.2, 5.5 Hz, 1H),3.42 (dd, J=15.2, 7.6 Hz, 1H), 3.18 (dd, J=13.0, 3.6 Hz, 1H), 3.10-3.04(m, 2H), 2.93-2.84 (m, 2H), 2.24 (q, J=7.6 Hz, 2H), 1.32 (d, J=6.9 Hz,6H), 1.08 (t, J=7.6 Hz, 3H). ¹³C NMR (101 MHz, MeOD) δ 175.96, 171.68,167.04, 150.86, 146.74, 136.78, 135.18, 128.77, 128.31, 126.58, 125.27,121.31, 118.64, 52.86, 49.38, 43.08, 37.43, 34.73, 34.07, 28.49, 23.14,8.60. UPLC-MS (ESI-MS) m/z: calculated for C₂₅H₃₃N₄O₂S⁺ 453.23, found453.24 [M+H]⁺.

Using methods described above, and the intermediate Fmoc-protected aminoacids and 2-azidoethylamines described above, the following compoundswere also synthesized.

(S)—N—((S)-1-amino-2-cyclopentylethyl)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamide6bCPPr: MS found: 423.3.

(S)—N—((S)-1-amino-2-cyclohexylethyl)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamide6bCHPr: 1H NMR (400 MHz, MeOD) δ 8.02 (d, J=1.9 Hz, 1H), 7.90 (d, J=8.7Hz, 1H), 7.51 (dd, J=8.7, 2.1 Hz, 1H), 4.94-4.90 (m, 1H), 3.95-3.90 (m,1H), 3.71 (dd, J=15.4, 5.6 Hz, 1H), 3.57 (dd, J=15.4, 7.5 Hz, 1H), 3.24(dd, J=13.0, 3.2 Hz, 1H), 3.05-2.93 (m, 1H), 2.30 (q, J=7.6 Hz, 2H),1.82-1.60 (m, 5H), 1.58-1.45 (m, 1H), 1.37-0.84 (m, 8H).

¹³C NMR (101 MHz, MeOD) δ 176.15, 171.83, 168.87, 151.32, 136.44,130.95, 126.73, 122.77, 121.21, 52.90, 52.51, 41.57, 39.61, 34.53,29.40, 28.56, 28.24, 25.73, 25.51, 25.46, 8.71.

(S)—N—((S)-1-amino-3-cyclohexylpropan-1-yl)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamide6bCHMPr: MS found: 451.5.

(S)—N—((S)-1-amino-3-phenylpropan-1-yl)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamide6bBnPr: 1H NMR (400 MHz, MeOD) δ 8.02 (d, J=2.0 Hz, 1H), 7.88 (d, J=8.7Hz, 1H), 7.51 (dd, J=8.7, 2.1 Hz, 1H), 7.38-7.14 (m, 5H), 4.84-4.82 (m,1H), 4.46-4.32 (m, 1H), 3.59 (dd, J=15.4, 5.3 Hz, 1H), 3.43 (dd, J=15.4,8.1 Hz, 1H), 3.17 (dd, J=13.0, 3.8 Hz, 1H), 3.08 (dd, J=12.9, 10.2 Hz,1H), 2.98-2.79 (m, 2H), 2.24 (q, J=7.6 Hz, 2H), 1.07 (t, J=7.6 Hz, 3H).¹³C NMR (101 MHz, MeOD) δ 176.05 (s), 171.66 (s), 168.80 (s), 151.27(s), 136.79 (s), 136.46 (s), 130.93 (s), 128.79 (s), 128.31 (s), 126.65(d, J=13.1 Hz), 122.76 (s), 121.21 (s), 52.76 (s), 49.42 (s), 42.95 (s),37.43 (s), 34.72 (s), 28.50 (s), 8.59 (s).

(S)—N—((S)-1-amino-2-cyclohexylethyl)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-isobutanamidopropanamide6bNoIB: 1H NMR (400 MHz, MeOD) δ 7.85 (d, J=8.5 Hz, 1H), 7.83 (s, 1H),7.42 (d, J=8.5 Hz, 1H), 4.84-4.77 (m, 1H), 3.66 (dd, J=15.0, 5.3 Hz,1H), 3.51 (dd, J=13.8, 8.0 Hz, 3H), 3.17-2.99 (m, 3H), 2.52 (dt, J=13.7,6.8 Hz, 1H), 1.40-1.27 (m, 6H), 1.16-0.99 (m, 6H).

(S)—N—((S)-1-amino-2-cyclohexylethyl)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-cyclopropylcarboxamidopropanamide6bNoCPr: 1H NMR (400 MHz, MeOD) δ 8.41 (t, J=5.5 Hz, 1H), 7.86 (d, J=8.5Hz, 1H), 7.83 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 4.82 (dd, J=7.8, 5.8 Hz,1H), 3.66 (dd, J=15.1, 5.8 Hz, 1H), 3.55-3.47 (m, 3H), 3.17-2.97 (m,3H), 1.80-1.59 (m, 1H), 1.33 (d, J=6.9 Hz, 6H), 0.95-0.73 (m, 4H).

(S)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-(5-isopropyl-4-methylthiazol-2-yl)-2-propionamidopropanamide.6tBnPr: 1H NMR (400 MHz, MeOD) δ 7.36-7.29 (m, 2H), 7.28-7.21 (m, 3H),4.64 (dd, J=8.0, 5.1 Hz, 1H), 4.47-4.26 (m, 1H), 3.44 (dd, J=15.1, 5.1Hz, 1H), 3.28-3.22 (m, 2H), 3.16 (dd, J=13.0, 3.6 Hz, 1H), 3.06 (dd,J=12.9, 10.4 Hz, 1H), 2.90 (dd, J=7.4, 3.4 Hz, 2H), 2.34 (d, J=6.4 Hz,3H), 2.23 (q, J=7.6 Hz, 2H), 1.28 (dd, J=6.8, 2.0 Hz, 6H), 1.09 (t,J=7.6 Hz, 3H).

(S)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-(5-(4-fluorophenyl)-4-methylthiazol-2-yl)-2-propionamidopropanamide.6xBnPr: 1H NMR (400 MHz, MeOD) δ 7.54-7.39 (m, 2H), 7.34-7.30 (m, 2H),7.27-7.19 (m, 5H), 4.69 (dd, J=7.9, 5.2 Hz, 1H), 4.51-4.30 (m, 1H), 3.45(dd, J=15.1, 5.1 Hz, 1H), 3.28 (dd, J=15.1, 7.9 Hz, 1H), 3.18 (dd,J=13.0, 3.6 Hz, 1H), 3.12-3.01 (m, 1H), 2.91 (dd, J=7.4, 3.9 Hz, 2H),2.40 (s, 3H), 2.26 (q, J=7.4 Hz, 2H), 1.10 (t, J=7.6 Hz, 3H).

(S)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-(5-phenyl-4-methylthiazol-2-yl)-2-propionamidopropanamide.6uBnPr: 1H NMR (400 MHz, MeOD) δ 7.50-7.37 (m, 5H), 7.34-7.28 (m, 2H),7.28-7.17 (m, 3H), 4.70 (dd, J=7.8, 5.2 Hz, 1H), 4.48-4.33 (m, 1H), 3.47(dd, J=15.1, 5.2 Hz, 1H), 3.32-3.25 (m, 1H), 3.18 (dd, J=13.0, 3.6 Hz,1H), 3.09 (dd, J=12.9, 10.4 Hz, 1H), 2.91 (dd, J=7.4, 3.3 Hz, 2H), 2.43(s, 3H), 2.26 (dt, J=15.0, 7.4 Hz, 2H), 1.10 (t, J=7.6 Hz, 3H).

(S)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-(5-(4-chlorophenyl)-4-methylthiazol-2-yl)-2-propionamidopropanamide.6wBnPr: 1H NMR (400 MHz, MeOD) δ 7.54-7.45 (m, 2H), 7.44-7.39 (m, 2H),7.35-7.28 (m, 2H), 7.28-7.18 (m, 3H), 4.69 (dd, J=7.9, 5.2 Hz, 1H),4.48-4.32 (m, 1H), 3.45 (dd, J=15.1, 5.1 Hz, 1H), 3.28 (dd, J=15.1, 7.9Hz, 1H), 3.18 (dd, J=13.0, 3.6 Hz, 1H), 3.08 (dd, J=12.9, 10.4 Hz, 1H),2.91 (dd, J=7.4, 3.7 Hz, 2H), 2.42 (s, 3H), 2.25 (q, J=7.5 Hz, 2H), 1.10(t, J=7.6 Hz, 3H).

(S)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-(5-(3-chlorophenyl)-4-methylthiazol-2-yl)-2-propionamidopropanamide.6sBnPr: 1H NMR (400 MHz, MeOD) δ 7.54-7.40 (m, 3H), 7.39-7.29 (m, 3H),7.28-7.15 (m, 3H), 4.70 (dd, J=7.8, 5.2 Hz, 1H), 4.42-4.39 (m, 1H), 3.45(dd, J=15.1, 5.2 Hz, 1H), 3.31-3.23 (m, 1H), 3.18 (dd, J=13.0, 3.4 Hz,1H), 3.07 (dd, J=15.8, 7.6 Hz, 1H), 2.98-2.84 (m, 2H), 2.43 (s, 3H),2.26 (q, J=7.6 Hz, 2H), 1.10 (t, J=7.6 Hz, 3H).

(S)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-(5-(2-chlorophenyl)-4-methylthiazol-2-yl)-2-propionamidopropanamide.6vBnPr: ¹H NMR (400 MHz, MeOD) δ 7.59-7.53 (m, 1H), 7.48-7.37 (m, 3H),7.35-7.19 (m, 5H), 4.59 (dd, J=8.5, 5.8 Hz, 1H), 4.49-4.32 (m, 1H),3.22-3.09 (m, 3H), 3.00 (dd, J=12.9, 10.6 Hz, 1H), 2.92 (dd, J=13.9, 6.4Hz, 1H), 2.82 (dd, J=13.9, 8.7 Hz, 1H), 2.34-2.16 (m, 5H), 1.10 (t,J=7.6 Hz, 3H).

(S)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-(5-(4-cyanophenyl)-4-methylthiazol-2-yl)-2-propionamidopropanamide.6yBnPr: ¹H NMR (400 MHz, MeOD) δ 7.92-7.78 (m, 2H), 7.68-7.59 (m, 2H),7.37-7.28 (m, 2H), 7.28-7.18 (m, 3H), 4.71 (dd, J=8.1, 5.1 Hz, 1H),4.41-4.38 (m, 1H), 3.46 (dd, J=15.2, 5.1 Hz, 1H), 3.31-3.25 (m, 1H),3.18 (dd, J=13.1, 3.7 Hz, 1H), 3.11-3.02 (m, 1H), 2.92-2.90 (m, 2H),2.47 (s, 3H), 2.25 (q, J=7.5 Hz, 2H), 1.10 (t, J=7.6 Hz, 3H).

(S)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-(5-(4-nitrophenyl)-4-methylthiazol-2-yl)-2-propionamidopropanamide.6zBnPr: ¹H NMR (400 MHz, MeOD) δ 8.47-8.26 (m, 2H), 7.79-7.56 (m, 2H),7.38-7.29 (m, 2H), 7.25 (dd, J=7.5, 4.2 Hz, 2H), 4.72 (dd, J=8.1, 5.1Hz, 1H), 4.40 (d, J=6.9 Hz, 1H), 3.47 (dd, J=15.2, 5.1 Hz, 1H),3.32-3.26 (m, 1H), 3.18 (dd, J=13.0, 3.6 Hz, 1H), 3.13-3.03 (m, 1H),2.91 (dd, J=7.4, 3.8 Hz, 2H), 2.49 (s, 3H), 2.26 (q, J=7.6 Hz, 2H), 1.10(t, J=7.6 Hz, 3H).

(S)—N—((S)-1-amino-2-cyclohexylethyl)-3-(5-(3-chlorophenyl)-4-methylthiazol-2-yl)-2-propionamidopropanamide.6sCHPr: ¹H NMR (400 MHz, MeOD) δ 7.52-7.33 (m, 4H), 4.82-4.81 (m, 1H),3.75-3.68 (m, 1H), 3.61-3.58 (m, 2H), 3.51 (dd, J=15.0, 5.6 Hz, 1H),3.38-3.36 (m, 1H), 2.45 (s, 3H), 2.29 (q, J=7.6 Hz, 2H), 1.81-1.55 (m,6H), 1.31-0.98 (m, 8H).

¹³C NMR (101 MHz, MeOD) δ 175.58, 170.92, 164.54, 147.55, 134.34,133.56, 130.71, 130.08, 128.54, 127.77, 127.24, 61.30, 56.07, 53.03,38.27, 34.52, 29.68, 28.64, 28.51, 26.04, 25.85, 14.43, 8.88.

Synthesis of Imidazolo[1,2-a]pyridine-2-yl Derivatives

These compounds were synthesized using the synthetic route shown above,and a representative example is described below.

(S)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-(5-chloroimidazolo[1,2-a]pyrid-2-yl)-2-propionamidopropanamide:¹H NMR (400 MHz, MeOD) δ 8.89 (d, J=0.8 Hz, 1H), 7.87-7.84 (m, 3H),7.35-7.16 (m, 5H), 4.70 (dd, J=8.4, 5.4 Hz, 1H), 4.42-4.35 (m, 1H),3.24-2.99 (m, 4H), 2.91 (d, J=7.5 Hz, 2H), 2.22 (q, J=7.6 Hz, 2H), 1.05(td, J=7.5, 0.6 Hz, 3H). ¹³C NMR (101 MHz, MeOD) δ 176.06, 171.65,139.36, 136.91, 136.30, 132.72, 128.84, 128.27, 126.54, 126.31, 124.21,113.31, 112.91, 52.51, 49.47, 42.73, 37.41, 28.35, 27.52, 8.50.

N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)piperidine-4-carboxamide 9aCHPr46: Compound 6aCHPr (150 mg, 0.34 mmol, 1equiv.) was added to a solution of the1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (93 mg, 0.40 mmol,1.2 equiv.), HBTU (192 mg, 0.51 mmol, 1.5 equiv.) and DIEA (176 μL, 1.01mmol, 3 equiv.) in DCM (10 mL). The resultant mixture was stirred atroom temperature for 1 h and concentrated. The residue was dissolve inEtOAc and washed with H₂O, saturated sodium bicarbonate, 1.0 M HCl,brine and dried over sodium sulfate. After removal of the solvent undervacuum, the residue was treated with TFA (2 ml) in DCM (10 mL) andstirred for 5 h. This reaction mixture was concentrated and purified byHPLC to afford 9aCHPr46 (139 mg, 74%). ¹H NMR (400 MHz, MeOD) δ 7.87 (d,J=8.5 Hz, 1H), 7.83 (s, 1H), 7.42 (dd, J=8.5, 1.5 Hz, 1H), 4.89 (dd,J=7.8, 5.4 Hz, 1H), 3.80 (ddd, J=10.2, 7.0, 3.5 Hz, 1H), 3.63 (dd,J=15.4, 5.5 Hz, 1H), 3.53-3.36 (m, 4H), 3.12-3.04 (m, 2H), 2.98-2.90 (m,2H), 2.49-2.38 (m, 1H), 2.32 (q, J=7.6 Hz, 2H), 1.98-1.81 (m, 4H),1.72-1.62 (m, 5H), 1.39-0.92 (m, 15H). ¹³C NMR (101 MHz, MeOD) δ 175.87,174.55, 171.35, 167.22, 150.93, 146.73, 135.21, 125.25, 121.57, 118.63,54.31, 53.02, 42.89, 40.66, 39.79, 39.39, 34.95, 34.08, 29.54, 28.66,28.32, 25.89, 25.72, 25.66, 25.14, 25.08, 23.16, 8.70. UPLC-MS (ESI-MS)m/z: calculated for C₃₀H₄₆N₅₀O₃S⁺ 556.33, found 556.22 [M+H]⁺.

N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)azetidine-3-carboxamide 9aCHPr34: Compound 9aCHPr34 was made fromcompound 6aCHPr and 1-(tert-butoxycarbonyl)azetidine-4-carboxylic acidas described above for compound 9aCHPr46. ¹H NMR (400 MHz, MeOD) δ 7.86(d, J=8.4 Hz, 1H), 7.82 (d, J=0.5 Hz, 1H), 7.42 (dd, J=8.4, 0.5 Hz, 1H),4.85 (dd, J=7.7, 5.3 Hz, 1H), 4.31-4.11 (m, 4H), 3.87-3.76 (m, 1H),3.67-3.55 (m, 2H), 3.53-3.46 (m, 2H), 3.15 (dd, J=13.7, 10.0 Hz, 1H),3.06 (dt, J=13.8, 6.9 Hz, 1H), 2.34 (dt, J=15.0, 4.2 Hz, 2H), 1.71-1.60(m, 5H), 1.38-0.88 (m, 15H).

N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)piperidine-4-sulfonamide 9aCHPrS46: Compound 9aCHPrS46 was made fromCompound 6aCHPr and 1-(tert-butoxycarbonyl)piperidine-4-sulfonylchloride in the presence of DIPEA, followed by TFA/DCM deprotection andHPLC purification. ¹H NMR (400 MHz, MeOD) δ 7.89 (d, J=8.5 Hz, 1H), 7.82(d, J=0.6 Hz, 1H), 7.79 (d, J=9.4 Hz, 1H), 7.41 (dd, J=8.4, 1.4 Hz, 1H),4.94-4.90 (m, 1H), 3.78-3.65 (m, 2H), 3.54-3.46 (m, 3H), 3.39-3.35 (m,2H), 3.29-3.22 (m, 1H), 3.16-3.02 (m, 4H), 2.37-2.23 (m, 4H), 1.99-1.91(m, 2H), 1.69 (dd, J=25.9, 10.8 Hz, 6H), 1.35-0.94 (m, 15H). Not in DBbut I added it at end.

N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)-N′-piperidin-4-ylurea 9aCHPrU46. Compound 9aCHPrU46 was made from Compound 6aCHPr and1-(tert-butoxycarbonyl)piperidin-4-yl isocyanate, followed by TFA/DCMdeprotection and HPLC purification. ¹H NMR (400 MHz, MeOD) δ 7.86 (d,J=8.5 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.41 (dd, J=8.5, 1.7 Hz, 1H),4.94-4.90 (m, 1H), 3.80-3.69 (m, 2H), 3.61 (dd, J=15.3, 4.9 Hz, 1H),3.48 (dd, J=15.3, 8.5 Hz, 1H), 3.42-3.34 (m, 3H), 3.18-2.99 (m, 4H),2.30 (q, J=7.5 Hz, 2H), 2.14-2.08 (m, 2H), 1.78-1.54 (m, 7H), 1.41-0.93(m, 15H).

N1-((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)-1,2,3-triazol-4-ylmethylamine9aCHPrTZ. Compound 9aCHPrTZ was made from Compound 5aCHPr andN-(tert-butoxycarbonyl) propargylamine in presence of Cu^(I) catalyst,followed by TFA/DCM deprotection and HPLC purification. 1H NMR (400 MHz,MeOD) δ 7.97 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.82 (d, J=1.5 Hz, 1H),7.42 (dd, J=8.5, 1.6 Hz, 1H), 4.75 (dd, J=8.8, 4.6 Hz, 1H), 4.69 (dd,J=14.0, 3.9 Hz, 1H), 4.45 (dd, J=14.0, 10.1 Hz, 1H), 4.23 (s, 2H),4.16-4.12 (m, 1H), 3.46 (dd, J=15.5, 4.6 Hz, 1H), 3.41-3.34 (m, 1H),3.07 (dt, J=13.8, 6.9 Hz, 1H), 2.37-2.23 (m, 2H), 1.85-1.61 (m, 5H),1.55-1.47 (m, 1H), 1.37-0.94 (m, 15H).

C. Synthesis of Final Compounds Example 1

N—((S)-2-((S)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-3-phenylpropyl)acrylamide:Compound 6bBnPr (40 mg, 0.09 mmol, 1 equiv.) was added to a solution ofacrylic acid (8 mg, 0.11 mmol, 1.2 equiv.), HBTU (51 mg, 0.13 mmol, 1.5equiv.) and DIEA (47 μL, 0.27 mmol, 3 equiv.) in DCM (5 mL). Theresultant mixture was stirred at room temperature for 1 h andconcentrated. The residue was purified by HPLC to afford Example 1 (37mg, 81%). ¹H NMR (400 MHz, MeOD:CCl3D=1:1) δ 7.88 (d, J=1.8 Hz, 1H),7.82 (d, J=8.7 Hz, 1H), 7.44 (dd, J=8.7, 2.1 Hz, 1H), 7.29-7.11 (m, 5H),6.21-6.08 (m, 2H), 5.59 (dd, J=9.7, 2.2 Hz, 1H), 4.80 (dd, J=7.5, 5.6Hz, 1H), 4.22-4.15 (m, 1H), 3.53 (dd, J=15.2, 5.6 Hz, 1H), 3.44-3.34 (m,3H), 2.80 (d, J=7.1 Hz, 2H), 2.22 (q, J=7.6 Hz, 2H), 1.07 (t, J=7.6 Hz,3H).

Example 2

(E)-N—((S)-2-((S)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-3-phenylpropyl)-4-(dimethylamino)but-2-enamide.Example 2 was prepared from Compound 6bBnPr by a similar procedure asthat described for Example 1. ¹H NMR (400 MHz, MeOD) δ 8.01 (d, J=2.0Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.50 (dd, J=8.7, 2.1 Hz, 1H), 7.35-7.11(m, 5H), 6.69 (dt, J=14.9, 7.3 Hz, 1H), 6.33 (d, J=15.3 Hz, 1H), 4.82(dd, J=8.8, 5.1 Hz, 1H), 4.37-4.17 (m, 1H), 3.90 (d, J=6.9 Hz, 2H), 3.53(dd, J=15.3, 5.1 Hz, 1H), 3.47 (dd, J=13.7, 4.6 Hz, 1H), 3.40-3.34 (m,2H), 2.90 (s, 6H), 2.88-2.74 (m, 2H), 2.25 (q, J=7.6 Hz, 2H), 1.06 (t,J=7.6 Hz, 3H).

Example 3

N—((S)-2-((S)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-3-phenylpropyl)-2-(morpholinomethyl)acrylamide:Example 3 was prepared from Compound 6bBnPr by a similar procedure asthat described for Example 1. ¹H NMR (400 MHz, MeOD) δ 8.01 (d, J=1.8Hz, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.51 (dd, J=8.7, 2.1 Hz, 1H), 7.35-7.08(m, 5H), 6.18 (s, 1H), 5.96 (s, 1H), 4.81 (dd, J=8.6, 5.3 Hz, 1H),4.43-4.30 (m, 1H), 4.12-3.73 (m, 6H), 3.62-3.34 (m, 5H), 3.32-3.03 (m,3H), 2.89-2.78 (m, 2H), 2.29 (tt, J=7.7, 4.0 Hz, 2H), 1.08 (t, J=7.6 Hz,3H). ¹³C NMR (101 MHz, MeOD) δ 175.95, 171.33, 171.25, 168.78, 167.42,151.30, 137.72, 136.48, 132.70, 130.89, 128.94, 128.82, 128.11, 126.70,126.22, 122.91, 121.19, 63.47, 58.50, 52.95, 51.80, 51.18, 43.00, 37.76,34.91, 28.63, 8.66.

Example 4

N—((S)-2-((S)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-2-cyclohexylethyl)-2-(morpholinomethyl)acrylamide:Example 4 was prepared from Compound 6bCHPr by a similar procedure asthat described for Example 1. ¹H NMR (400 MHz, MeOD) δ 8.04 (d, J=1.9Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.52 (dd, J=8.7, 2.1 Hz, 1H), 6.19 (s,1H), 5.96 (s, 1H), 4.90-4.88 (m, 1H), 4.24-3.74 (m, 6H), 3.64 (dd,J=15.5, 5.4 Hz, 1H), 3.60-3.34 (m, 6H), 3.30-3.00 (m, 3H), 2.34 (qd,J=7.6, 1.4 Hz, 2H), 1.75-1.65 (m, 5H), 1.50-1.39 (m, 1H), 1.36-0.80 (m,8H).

Example 5

N—((S)-2-((S)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-3-cyclohexylpropyl)-2-(morpholinomethyl)acrylamide:Example 5 was prepared from Compound 6bCHMPr by a similar procedure asthat described for Example 1. ¹H NMR (400 MHz, MeOD) δ 8.04 (d, J=1.8Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.52 (dd, J=8.7, 2.1 Hz, 1H), 6.20 (s,1H), 5.96 (s, 1H), 4.85-4.79 (m, 1H), 4.25-4.18 (m, 1H), 4.06-3.87 (m,5H), 3.65-3.35 (m, 7H), 3.17-3.11 (m, 3H), 2.33 (qd, J=7.6, 1.2 Hz, 2H),1.79-1.60 (m, 5H), 1.50-0.62 (m, 11H).

Example 6

N—((S)-2-((S)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-2-cyclopentylethyl)-2-(morpholinomethyl)acrylamide:Example 6 was prepared from Compound 6bCPPr by a similar procedure asthat described for Example 1. 1H NMR (400 MHz, MeOD) δ 8.04 (d, J=2.1Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.52 (dd, J=8.7, 2.1 Hz, 1H), 6.18 (s,1H), 5.94 (s, 1H), 4.94-4.92 (m, 1H), 4.25-3.74 (m, 6H), 3.64 (dd,J=15.4, 5.5 Hz, 1H), 3.56-3.36 (m, 6H), 3.24-3.15 (m, 3H), 2.42-2.24 (m,2H), 2.01-1.90 (m, 1H), 1.88-1.77 (m, 1H), 1.74-1.44 (m, 4H), 1.43-1.03(m, 6H).

Example 7

N—((S)-2-((S)-3-(6-prop-2-ylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-3-phenylpropyl)-2-(morpholinomethyl)acrylamide:Example 7 was prepared from Compound 6aBnPr by a similar procedure asthat described for Example 1. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J=8.5Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.42 (dd, J=8.5, 1.6 Hz, 1H), 7.35-7.03(m, 5H), 6.19 (s, 1H), 5.95 (s, 1H), 4.78 (dd, J=8.5, 5.4 Hz, 1H),4.45-4.28 (m, 1H), 4.18-3.67 (m, 6H), 3.56-3.38 (m, 4H), 3.31-3.23 (m,2H), 3.21-2.98 (m, 3H), 2.90-2.73 (m, 2H), 2.28 (q, J=7.6 Hz, 2H), 1.33(d, J=6.9 Hz, 6H), 1.09 (t, J=7.6 Hz, 3H). ¹³C NMR (101 MHz, MeOD) δ175.91, 171.34, 167.40, 167.05, 150.91, 146.70, 137.72, 135.22, 132.71,128.97, 128.82, 128.10, 126.21, 125.22, 121.53, 118.61, 63.44, 58.47,53.16, 51.80, 51.14, 43.04, 37.76, 34.91, 34.08, 28.63, 23.16, 8.65.

Example 8

N—((S)-2-((S)-3-(6-ethylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-3-phenylpropyl)-2-(morpholinomethyl)acrylamide:Example 8 was prepared from Compound 6iBnPr by a similar procedure asthat described for Example 1. 1H NMR (400 MHz, MeOD) δ 7.83 (d, J=8.4Hz, 1H), 7.78 (s, 1H), 7.38 (dd, J=8.4, 1.6 Hz, 1H), 7.32-7.17 (m, 4H),6.18 (s, 1H), 5.94 (s, 1H), 4.78 (dd, J=8.5, 5.5 Hz, 1H), 4.38-4.35 (m,1H), 4.18-3.65 (m, 6H), 3.56-3.39 (m, 3H), 3.31-2.99 (m, 6H), 2.91-2.75(m, 3H), 2.28 (q, J=7.6 Hz, 2H), 1.31 (t, J=7.6 Hz, 3H), 1.09 (t, J=7.6Hz, 3H).

Example 9

(DI-1548).N—((S)-2-((S)-3-(6-prop-2-ypbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-2-cyclohexylethyl)-2-(morpholinomethyl)acrylamide:Example 9 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ¹H NMR (400 MHz, MeOD) δ 7.85 (d, J=8.5Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.42 (dd, J=8.5, 1.7 Hz, 1H), 6.20 (s,1H), 5.96 (s, 1H), 4.85 (dd, J=7.7, 5.5 Hz, 1H), 4.16-3.73 (m, 7H), 3.62(dd, J=15.3, 5.5 Hz, 1H), 3.54-3.43 (m, 4H), 3.29-2.95 (m, 4H), 2.34(qd, J=7.6, 0.9 Hz, 2H), 2.34 (qd, J=7.6, 0.9 Hz, 2H), 1.72 (t, J=12.5Hz, 2H), ¹H NMR (400 MHz, MeOD) δ 7.85 (d, J=8.5 Hz, 1H), 7.82 (d, J=1.7Hz, 1H), 7.42 (dd, J=8.5, 1.7 Hz, 1H), 6.20 (s, 1H), 5.96 (s, 1H), 4.85(dd, J=7.7, 5.5 Hz, 1H), 4.16-3.73 (m, 7H), 3.62 (dd, J=15.3, 5.5 Hz,1H), 3.54-3.43 (m, 4H), 3.29-2.95 (m, 4H), 2.34 (qd, J=7.6, 0.9 Hz, 2H),1.80-1.56 (m, 5H), 1.53-1.36 (m, 1H), 1.32 (d, J=6.9 Hz, 6H), 1.26-0.80(m, 8H).

Example 10

N—((S)-2-((S)-3-(6-prop-2-ypbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-2-cyclohexylethyl)-2-(2-morpholinoethyl)acrylamide:Example 10 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1.1H NMR (400 MHz, MeOD) δ 7.85 (d, J=8.5 Hz,1H), 7.83 (d, J=1.7 Hz, 1H), 7.42 (dd, J=8.5, 1.7 Hz, 1H), 5.77 (s, 1H),5.53 (s, 1H), 4.86 (dd, J=7.7, 5.9 Hz, 1H), 4.09-4.05 (m, 2H), 3.96-3.91(m, 1H), 3.78 (t, J=12.5 Hz, 2H), 3.68-3.49 (m, 4H), 3.43 (dd, J=15.3,7.8 Hz, 1H), 3.24 (t, J=7.0 Hz, 2H), 3.19-2.99 (m, 4H), 2.76-2.69 (dt,J=13.9, 6.8 Hz, 1H), 2.67-2.54 (m, 1H), 2.30 (q, J=7.6 Hz, 2H),1.82-1.58 (m, 5H), 1.51-1.39 (m, 1H), 1.33 (d, J=6.9 Hz, 6H), 1.27-0.87(m, 8H).

Example 11

(E)-N—((S)-2-((S)-3-(6-prop-2-ylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-3-phenylpropyl)-4-(dimethylamino)but-2-enamide.Example 11 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 11H NMR (400 MHz, MeOD) δ 7.85 (d, J=8.5 Hz,1H), 7.82 (d, J=1.7 Hz, 1H), 7.42 (dd, J=8.5, 1.7 Hz, 1H), 6.75-6.63 (m,1H), 6.35 (dt, J=15.3, 1.1 Hz, 1H), 4.86-4.82 (m, 1H), 3.90 (dd, J=7.3,1.2 Hz, 2H), 3.85-3.80 (m, 1H), 3.59 (dd, J=15.3, 5.1 Hz, 1H), 3.53 (dd,J=13.7, 4.0 Hz, 1H), 3.46 (dd, J=15.3, 8.2 Hz, 1H), 3.32-3.24 (m, 1H),3.11-3.04 (m, 1H), 2.90 (s, 6H), 2.37-2.26 (m, 2H), 1.79-1.57 (m, 5H),1.47-1.41 (m, 1H), 1.32 (d, J=6.9 Hz, 6H), 1.28-0.88 (m, 8H).

Example 12

N—((S)-2-((S)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-3-phenylpropyl)-1-methyl-1,2,5,6-tetrahydropyridine-3-carboxamide:Example 12 was prepared from Compound 6bBnPr by a similar procedure asthat described for Example 1. ¹H NMR (400 MHz, MeOD) δ 8.08-7.98 (m,1H), 7.94-7.84 (m, 1H), 7.51 (dd, J=8.7, 2.1 Hz, 1H), 7.33-7.11 (m, 5H),6.67 (s, 1H), 4.82 (dd, J=8.7, 5.2 Hz, 1H), 4.32-4.25 (m, 1H), 3.83-3.33(m, 7H), 3.24-3.07 (m, 1H), 3.00 (s, 3H), 2.89-2.75 (m, 2H), 2.59 (s,2H), 2.25 (q, J=7.6 Hz, 2H), 1.07 (t, J=7.6 Hz, 3H).

Example 13

N—((S)-2-((S)-3-(6-prop-2-ylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-3-phenylpropyl)-1-methyl-1,2,5,6-tetrahydropyridine-3-carboxamide:Example 13 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. 1H NMR (400 MHz, MeOD) δ 7.85 (d, J=8.5Hz, 1H), 7.83 (d, J=1.7 Hz, 1H), 7.42 (dd, J=8.5, 1.7 Hz, 1H), 6.67 (s,1H), 4.86-4.84 (m, 1H), 4.23-4.15 (m, 1H), 3.89-3.39 (m, 6H), 3.30-3.03(m, 3H), 2.99 (s, 3H), 2.66-2.52 (m, 2H), 2.32 (qd, J=7.6, 1.0 Hz, 2H),1.71-1.63 (m, 5H), 1.47-1.39 (m, 1H), 1.33 (d, J=6.9 Hz, 6H), 1.26-0.83(m, 8H).

Example 14

N—((S)-2-((S)-3-(6-prop-2-ypbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-2-cyclohexylethyl)-2-(pyrrolidin-1-ylmethyl)acrylamide:Example 14 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. 1H NMR (400 MHz, MeOD) δ 7.85 (d, J=8.5Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.42 (dd, J=8.5, 1.7 Hz, 1H), 6.13 (s,1H), 5.93 (s, 1H), 4.85 (dd, J=7.7, 5.5 Hz, 1H), 3.98 (d, J=1.7 Hz, 2H),3.89-3.84 (m, 1H), 3.68-3.56 (m, 3H), 3.53-3.40 (m, 2H), 3.25 (dd,J=13.7, 10.4 Hz, 1H), 3.17-3.00 (m, 3H), 2.34 (qd, J=7.6, 1.7 Hz, 2H),2.20-1.99 (m, 4H), 1.78-1.56 (m, 5H), 1.48-1.38 (m, 1H), 1.32 (d, J=6.9Hz, 6H), 1.24-0.89 (m, 8H).

Example 15

N—((S)-2-((S)-3-(6-prop-2-ypbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-2-cyclohexylethyl)-2-(2-(dimethylamino)ethyl)acrylamide:Example 15 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ¹H NMR (400 MHz, MeOD) δ 7.85 (d, J=8.5Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.42 (dd, J=8.5, 1.7 Hz, 1H), 5.76 (s,1H), 5.52 (s, 1H), 4.87-4.84 (m, 1H), 3.92-3.87 (m, 1H), 3.65-3.52 (m,2H), 3.44 (dd, J=15.3, 7.8 Hz, 1H), 3.23 (t, J=7.2 Hz, 2H), 3.18-3.01(m, 2H), 2.93 (s, 6H), 2.77-2.55 (m, 2H), 2.31 (q, J=7.6 Hz, 2H),1.79-1.58 (m, 5H), 1.49-1.38 (m, 1H), 1.32 (d, J=6.9 Hz, 6H), 1.27-0.87(m, 8H).

Example 16

(E)-N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)-2-methyl-4-(4-methylpiperidin-1-yl)but-2-enamide:Example 16 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ¹H NMR (400 MHz, MeOD) δ 7.86-7.83 (m,2H), 7.42 (dd, J=8.5, 1.7 Hz, 1H), 6.23 (td, J=7.0, 1.4 Hz, 1H),4.86-4.83 (m, 1H), 3.87-3.82 (m, 1H), 3.63-3.56 (m, 3H), 3.53-3.41 (m,6H), 3.28-3.22 (m, 5H), 3.07 (dt, J=13.8, 6.9 Hz, 1H), 2.91 (s, 3H),2.34-2.28 (m, 2H), 1.89 (d, J=1.2 Hz, 3H), 1.80-1.58 (m, 5H), 1.49-1.40(m, 1H), 1.33 (d, J=6.9 Hz, 6H), 1.25-0.91 (m, 8H).

Example 17

N—((S)-2-((S)-3-(6-prop-2-ylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-3-phenylpropyl)-4-(dimethylamino)but-2-ynamide:Example 17 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ESI-MS m/z: calculated for C30H44N5O3S+554.3, found 554.5 [M+H]+.

Example 18

(S)—N—((S)-1-cyclohexyl-2-(vinylsulfonamido)ethyl)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamide:To a mixture of 6aCHPr (45 mg, 0.1 mmol) and DIEA (47 μL) in DCM (5 mL)was added ethenesulfonyl chloride (15 mg, 0.12 mmol) at 0° C. Theresulting mixture was stirred at room temperature for 1 h andconcentrated. The residue was purified by HPLC to yield Example 18.ESI-MS m/z: calculated for C26H39N4O4S2+ 535.2, found 535.3 [M+H]+.

Example 19

(S)—N—((S)-1-cyclohexyl-2-(ethynylsulfonamido)ethyl)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamide:Example 19 was prepared from 6aCHPr by a similar procedure as that forExample 18. ESI-MS m/z: calculated for C26H37N4O4S2+ 533.2, found 533.7[M+H]+.

Example 20

(S)—N—((S)-1-(2-chloroacetamido)-3-phenylpropan-2-yl)-3-(6-chlorobenzo[d]thiazol-2-yl)-2-propionamidopropanamide:Example 20 was prepared from Compound 6bBnPr by a similar procedure asthat described for Example 1. 1H NMR (400 MHz, MeOD:CCl3D=1:1) δ 7.86(d, J=1.8 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.44 (dd, J=8.7, 2.0 Hz, 1H),7.25-7.15 (m, 5H), 4.85-4.75 (m, 1H), 4.28-4.14 (m, 1H), 3.94 (s, 2H),3.52 (dd, J=15.3, 5.6 Hz, 1H), 3.44-3.36 (m, 2H), 3.31-3.23 (m, 1H),2.78 (d, J=7.1 Hz, 2H), 2.22 (q, J=7.6 Hz, 2H), 1.07 (t, J=7.6 Hz, 3H).

Example 21

(DI-1859):N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)-2-((dimethylamino)methyl)acrylamide.Example 21 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ¹H NMR (400 MHz, MeOD) δ 7.85 (d, J=8.5Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.41 (dd, J=8.5, 1.7 Hz, 1H), 6.18 (s,1H), 5.93 (s, 1H), 4.86 (dd, J=7.7, 5.5 Hz, 1H), 3.99-3.82 (m, 3H), 3.62(dd, J=15.3, 5.5 Hz, 1H), 3.53-3.43 (m, 2H), 3.24 (dd, J=13.7, 10.3 Hz,1H), 3.07 (dt, J=13.8, 6.9 Hz, 1H), 2.88 (s, 6H), 2.34 (qd, J=7.6, 1.5Hz, 2H), 1.79-1.57 (m, 5H), 1.47-1.38 (m, 1H), 1.32 (d, J=6.9 Hz, 6H),1.24-0.88 (m, 8H). ¹³C NMR (101 MHz, DMSO) δ 175.17, 170.62, 166.49,166.30, 150.15, 145.89, 134.37, 132.78, 127.28, 124.44, 120.76, 117.80,58.60, 53.62, 52.26, 41.33, 40.31, 38.94, 34.00, 33.28, 28.79, 27.89,27.61, 25.07, 24.86, 24.78, 22.36, 7.89. HRMS (ESI-MS) m/z: calculatedfor C₃₀H₄₆N₅O₃S⁺ 556.3316, found 556.3321 [M+H]⁺.

Example 22

(DI-1860):N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)-2-((diethylamino)methyl)acrylamide.Example 22 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ESI-MS m/z: calculated for C32H50N5O3S⁺584.4, found 584.7 [M+H]⁺.

Example 23

N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)-2-(piperidin-1-ylmethyl)acrylamide.Example 23 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ESI-MS m/z: calculated for C₃₃H₅₀N₅O₃S⁺596.4, found 596.5 [M+H]⁺.

Example 24

2-((1H-imidazol-1-yl)methyl)-N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)acrylamide.Example 24 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ¹H NMR (400 MHz, MeOD) δ 8.94 (t, J=1.4Hz, 1H), 7.91-7.75 (m, 2H), 7.62-7.56 (m, 1H), 7.56-7.50 (m, 1H),7.46-7.37 (m, 1H), 6.04 (s, 1H), 5.78 (s, 1H), 5.06 (q, J=14.7 Hz, 2H),4.85-4.83 (m, 1H), 3.83-3.78 (m, 1H), 3.58 (dd, J=15.2, 5.8 Hz, 1H),3.50 (dd, J=13.7, 3.7 Hz, 1H), 3.42 (dd, J=15.2, 7.8 Hz, 1H), 3.20-3.02(m, 2H), 2.30 (q, J=7.6 Hz, 2H), 1.80-1.54 (m, 5H), 1.42-1.35 (m, 1H),1.33 (d, J=6.9 Hz, 6H), 1.26-0.84 (m, 8H). ¹³C NMR (101 MHz, MeOD) δ175.77, 171.34, 167.08, 166.67, 150.97, 146.69, 137.93, 135.70, 135.23,125.21, 124.17, 122.01, 121.55, 119.66, 118.61, 54.22, 52.98, 50.10,41.11, 39.69, 34.91, 34.09, 29.56, 28.63, 28.31, 25.89, 25.71, 25.65,23.17, 23.15, 8.73. HRMS (ESI-MS) m/z: calculated for C₃₁H₄₃N₆O₃S⁺579.3112, found 579.3112 [M+H]⁺.

Example 25

2-(azetidin-1-ylmethyl)-N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)acrylamide.Example 25 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ESI-MS m/z: calculated for C₃₁H₄₆N₅O₃S⁺568.3, found 568.9 [M+H]⁺.

Example 26

N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)-2-((3,3-difluoroazetidin-1-yl)methyl)acrylamide.Example 26 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ESI-MS m/z: calculated for C₃₁H₄₄F₂N₅O₃S⁺604.3, found 604.4 [M+H]⁺.

Example 27

N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)-2-((4-methylpiperazin-1-yl)methyl)acrylamide.Example 27 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ESI-MS m/z: calculated for C₃₁H₅₁N₆O₃S⁺611.4, found 611.8 [M+H]⁺.

Example 28

N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)-2-((1,1-dioxidothiomorpholino)methyl)acrylamide.Example 28 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ESI-MS m/z: calculated for C₃₂H₄₈N₅O₅S₂ ⁺646.3, found 646.5 [M+H]⁺.

Example 29

N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)-2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)acrylamide.Example 29 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ESI-MS m/z: calculated for C₃₄H₅₃N₆O₄S⁺641.4, found 641.4 [M+H]⁺.

Example 30.N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)-2-((4,4-difluoropiperidin-1-yl)methyl)acrylamide

Example 30 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ESI-MS m/z: calculated for C₃₃H₄₈F₂N₅O₃S⁺632.3, found 632.6 [M+H]⁺.

Example 31.N—((S)-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-3-(pyridin-4-yl)propyl)acrylamide

Example 31 was prepared from by a similar procedure as that describedfor Example 1. ESI-MS m/z: calculated for C₂₇H₃₄N₅O₃S⁺ 508.2, found508.4 [M+H]⁺.

Example 32.N—((S)-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-3-(pyridin-3-yl)propyl)acrylamide

Example 32 was prepared from by a similar procedure as that describedfor Example 1. ESI-MS m/z: calculated for C₂₇H₃₄N₅O₃S⁺ 508.2, found508.3 [M+H]⁺.

Example 33

(S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamido-N—((S)-1-(pyridin-3-yl)-3-(vinylsulfonamido)propan-2-yl)propanamide.Example 33 was prepared from by a similar procedure as that describedfor Example 1. ESI-MS m/z: calculated for C₂₆H₃₄N₅O₄S₂ ⁺ 544.2, found544.3 [M+H]⁺.

Example 34

N—((S)-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)-3-(pyridin-3-yl)propyl)-2-(morpholinomethyl)acrylamide.Example 34 was prepared from by a similar procedure as that describedfor Example 1. ESI-MS m/z: calculated for C₃₂H₄₃N₆O₄S⁺ 607.3, found607.7 [M+H]⁺.

Example 35

N—((S)-2-((S)-3-(6-chloroimidazo[1,2-a]pyridin-2-yl)-2-propionamidopropanamido)-3-phenylpropyl)-2-(morpholinomethyl)acrylamide.Example 35 was prepared from by a similar procedure as that describedfor Example 1. ESI-MS m/z: calculated for C₃₀H₃₈ClN₆O₄ ⁺ 581.3, found581.5 [M+H]⁺.

Example 36

N—((S)-3-(4-fluorophenyl)-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)propyl)-2-(morpholinomethyl)acrylamide.Example 36 was prepared from by a similar procedure as that describedfor Example 1. ESI-MS m/z: calculated for C₃₃H₄₃FN₅O₄S⁺ 624.3.3, found624.7 [M+H]⁺.

Example 37

N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)acrylamide.Example 37 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J=8.4Hz, 1H), 7.71 (d, J=1.2 Hz, 1H), 7.50-7.31 (m, 2H), 6.96-6.94 (m, 2H),6.24 (dd, J=17.0, 1.3 Hz, 1H), 6.09 (dd, J=17.0, 10.2 Hz, 1H), 5.58 (dd,J=10.2, 1.2 Hz, 1H), 4.94-4.90 (m, 1H), 3.94-3.76 (m, 1H), 3.64 (dd,J=15.3, 4.8 Hz, 1H), 3.57-3.42 (m, 2H), 3.39-3.22 (m, 1H), 3.06 (dt,J=13.8, 6.9 Hz, 1H), 2.36 (q, J=7.6 Hz, 2H), 1.66-1.61 (m, 5H),1.45-1.27 (m, 7H), 1.25-0.83 (m, 8H). ¹³C NMR (101 MHz, CDCl₃) δ 174.43,170.68, 166.83, 166.52, 150.40, 146.95, 134.95, 130.71, 126.46, 125.82,121.80, 118.87, 54.66, 52.63, 41.77, 40.08, 35.45, 34.27, 29.62, 29.52,28.58, 26.07, 25.95, 25.89, 24.16, 9.61. HRMS (ESI-MS) m/z: calculatedfor C₂₇H39N₄O₃S⁺ 499.2737, found 499.2741 [M+H]⁺.

Example 38

(S)—N—((S)-2-(2-chloroacetamido)-1-cyclohexylethyl)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamide.Example 38 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J=8.4Hz, 1H), 7.70 (s, 1H), 7.45 (d, J=7.0 Hz, 1H), 7.37 (dd, J=8.4, 1.2 Hz,1H), 7.23-=7.14 (m, 1H), 7.02 (d, J=8.8 Hz, 1H), 4.95 (dd, J=11.3, 6.3Hz, 1H), 4.06 (d, J=14.9 Hz, 1H), 3.94 (d, J=15.0 Hz, 1H), 3.90-3.79 (m,1H), 3.69 (dd, J=15.6, 4.5 Hz, 1H), 3.48-3.28 (m, 3H), 3.06 (dt, J=13.7,6.8 Hz, 1H), 2.38 (q, J=7.5 Hz, 2H), 1.69-1.47 (m, 5H), 1.39-1.28 (m,7H), 1.22 (t, J=7.6 Hz, 3H), 1.15-0.77 (m, 5H). ¹³C NMR (101 MHz, CDCl₃)δ 174.27, 170.85, 167.29, 166.83, 150.82, 146.74, 135.05, 125.62,121.92, 118.83, 54.44, 52.24, 42.52, 41.72, 40.21, 35.32, 34.26, 29.66,29.44, 28.39, 26.02, 25.95, 25.87, 24.17, 9.53. HRMS (ESI-MS) m/z:calculated for C₂₆H₃₈ClN₄O₃S⁺ 521.2348, found 521.2350 [M+H]⁺.

Example 39

(E)-N—((S)-2-cyclohexyl-2-((S)-3-(6-isopropylbenzo[d]thiazol-2-yl)-2-propionamidopropanamido)ethyl)-4-morpholinobut-2-enamide.Example 39 was prepared from Compound 6aCHPr by a similar procedure asthat described for Example 1. ¹H NMR (400 MHz, MeOD) δ 7.86 (d, J=8.5Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.42 (dd, J=8.5, 1.7 Hz, 1H), 6.70 (dt,J=15.0, 7.4 Hz, 1H), 6.37 (d, J=15.3 Hz, 1H), 4.85 (dd, J=8.2, 5.1 Hz,1H), 4.16-3.91 (m, 4H), 3.85-3.76 (m, 3H), 3.59 (dd, J=15.3, 5.1 Hz,1H), 3.54-3.43 (m, 4H), 3.31-3.01 (m, 4H), 2.31 (q, J=7.6 Hz, 2H),1.73-1.61 (m, 5H), 1.49-1.39 (m, 1H), 1.32 (d, J=6.9 Hz, 6H), 1.25-0.90(m, 8H). ¹³C NMR (101 MHz, MeOD) δ 175.78, 171.38, 167.09, 165.21,150.95, 146.70, 135.23, 132.88, 129.03, 125.23, 121.57, 118.61, 63.70,56.84, 54.48, 53.08, 51.58, 40.53, 39.81, 35.10, 34.08, 29.52, 28.68,28.34, 25.89, 25.73, 25.67, 23.17, 23.15, 8.73. HRMS (ESI-MS) m/z:calculated for C₃₂H₄₈N₅O₄S⁺ 598.3422, found 598.3425 [M+H]⁺.

EXPERIMENTAL PROCEDURES Competitive FP Binding Assay

The Fluorescence Polarization (FP) competitive binding assays wereperformed to accurately determine the binding affinities of our DCN1inhibitors. A novel FAM labeled fluorescent probe compound (46) wasdesigned and synthesized based on one of our potent small molecule DCN1inhibitors. Equilibrium dissociation constants (K_(d)) values of 46 toboth DCN1 and DCN2 proteins were determined from protein saturationexperiments by monitoring the total FP values of mixtures composed withthe fluorescent probe at a fixed concentration and proteins withincreasing concentrations up to full saturation. Serial dilutions ofproteins were mixed with 46 to a final volume of 200 μl in the assaybuffer (100 mM phosphate buffer, pH=6.5, with 0.02% Tween-20 and 2%DMSO). Final probe concentration was 5 nM for both assays. Plates wereincubated at room temperature for 30 minutes with gentle shaking toassure equilibrium. FP values in millipolarization units (mP) weremeasured using the Infinite M-1000 plate reader (Tecan U.S., ResearchTriangle Park, N.C.) in Microfluor 1 96-well, black, round-bottom plates(Thermo Scientific, Waltham, Mass.) at an excitation wavelength of 485nm and an emission wavelength of 530 nm. K_(d) values of 46 werecalculated by fitting the sigmoidal dose-dependent FP increases as afunction of protein concentrations using Graphpad Prism 6.0 software(Graphpad Software, San Diego, Calif.).

Cloning and Purification of DCN Proteins

Human DCN1 (residues 58-259) were cloned into a pDEST17 plasmidcontaining an N-terminal His₆ tag. DCN2 (residues 62-259), DCN3(residues 86-304), DCN4 (residues 102-292) and DCN5 (residues 47-237)were cloned into an N-terminal His₆-TEV expression vector. Pure proteinswere derived from the same expression and purification protocols.Plasmids were transformed into Rosetta2 cells, the cells were grown inTerrific Broth at 37° C. to an O.D.₆₀₀>1.0 and induced with 0.4 mMIsopropyl β-D-1-thiogalactopyranoside overnight at 20° C. The pelletedcells were resuspended in lysis buffer containing 25 mM Tris-HCl, pH7.5, 200 mM NaCl and protease inhibitors, sonicated and centrifuged at34,000×g for 45 minutes to remove debris. Cleared lysate was incubatedwith Ni-NTA resin (Qiagen) prewashed with lysis buffer, for 1 hr at 4°C. The matrix was loaded into a column then washed with 25 mM Tris-HCl,pH 7.5, 200 mM NaCl and 10 mM imidazole. Protein was eluted with 25 mMTris-HCl, pH 7.5, 200 mM NaCl and 300 mM imidazole, concentrated andapplied to a Superdex 75 (GE Healthcare) column pre-equilibrated with 25mM Tris pH 7.5, 200 mM NaCl and 1 mM DTT. For DCN2-5, the N-terminalHis₆ tag was removed prior to gel filtration. Tag removal was achievedthrough incubation with TEV protease during overnight dialysis against25 mM Tris pH 7.5, 200 mM NaCl and 1 mM DTT and a second Ni-NTA column.DCN2-5 proteins were stored at −80° C. in 1 mg/mL fractions containing5% glycerol. The uncleaved DCN1 protein was stored at −80° C. withoutglycerol.

Cell Lines and Culture Conditions

Immortalized liver THLE2 (ATCC® CRL-2706™) cell lines was purchased fromthe ATCC (Rockville, Md.). The cell line was maintained in BEGMBronchial Epithelial Cell Growth Medium from Lonza/Clonetics Corporation(CC3170, Walkersville, Md.) supplemented with 10% FBS and pen-strep at37° C. in a humidified incubator with 5% CO₂. Esophageal cancer KYSE140cell line (ACC 348) was purchased from DSMZ (Braunschweig, Germany). Thecell line was maintained RPMI1640 supplemented with 10% FBS andpen-strep at 37° C. in a humidified incubator with 5% CO₂.

Western Blotting Analysis and Antibodies

Treated cells were lysed by RIPA buffer supplemented with proteaseinhibitor. The expression level of indicated proteins was examined bywestern blotting analysis. GAPDH was used as a loading control.Antibodies were purchased: Cullin 1 (sc-11384), Cullin2 (sc-10781),CullinS (sc-13014) and Cullin7 (sc-134565) from Santa Cruz Biotech.(Santa Cruz, Calif.); Cullin 4A (PA5-14542), Cullin 4B (PA5-35239),Cullin9 (PA5-20277), DCN2 (DCUNID2, PA5-31607) and DCN3 (DCUNID3,PA5-44000) from ThermoFisher Scientific (Wayne, Mich.); Cullin 3 (2759),NRF2 (12721), HO-1 (70081), NQO1 (3187), Cyclin E (4129), Bim (2819),Keap1 (8047) and UBC12 (4913) from Cell Signaling Technology (Boston,Mass.); DCN1 (GWB-E3D700) from GenWay Biotech (San Diego, Calif.).Results are representative of three independent experiments.

Mass Spectroscopy of DCN1 Protein Incubations

Recombinant DCN1 protein (380 μM) in 25 mM Tris 7.5, 200 mM NaCl, 1 mMDTT buffer was incubated with a 1.2 fold excess of selected DCN1inhibitors at 4° C. for overnight. The reaction mixture was diluted withtenfold with water, and the protein was analyzed by Q-TOF massspectroscopy. DCN1 untreated, or treated with previously describednon-covalent inhibitors produced an isotope deconvoluted peak at26.085.75 amus. Incubation under the described conditions with Examples4, 7 and 9 led to 95-99% ablation of the parent peak in the massspectrum, with a major (>90%) new peak appearing at 26588.96 amu(Dalton) for Example 4, 26604.34 amu for Example 7, and 26596.18 amu forExample 9. In each case this corresponds to addition of the inhibitor tothe protein, coupled with the loss of the morpholinyl group, from theinitial Michael adduct between the protein and the small molecule. Thedata are further shown in FIG. 2.

FIG. 2A shows DCN1 Apo-protein Mass is 26085.75 Da. The calculated massfrom protein sequence is 26.2 kDa.

FIG. 2B shows Apo-DCN1 plus Example 4 Mass is 26588.96 Da. Thedifference from DCN1 Apo-protein is 503.21 Da. The calculated molecularmass for Example 4 is 589.25 Da. The difference in compound mass is86.04 Da. The calculated molecular mass for the Morpholino group is87.07 Da.

FIG. 2C shows DCN1 plus Example 7 mass is 26604.34 Da. The differencefrom DCN1 Apo-protein is 518.59 Da. The calculated molecular mass forExample is 7605.3 Da. The difference in compound mass is 86.71 Da. Thecalculated molecular mass for Morpholino group is 87.07 Da.

FIG. 2D shows DCN1 plus Example 9 mass is 26596.56 Da. The differencefrom DCN1 apo-protein is 510.81 Da. The calculated molecular mass forExample 9 is 597.33 Da. The difference in compound mass is 86.52 Da. Thecalculated molecular mass for Morpholino group is 87.07 Da.

Analysis of the Effect of Covalent DCN1 Inhibitors in Mice

The effect of several representative covalent DCN1 inhibitors (Examples9, 21 and 22) on the level of Nrf2 protein in mouse liver was examined.Mice were administered with a single dose of Example 9 (DI-1548),Example 21 (DI-1859) or Example 22 (DI-1860) at 25 mg/kg, orphosphate-buffered saline (PBS), all via intraperitoneal (IP) injection.Mice were sacrificed at different time points and liver tissues wereharvested for western blotting analysis for Nrf2 protein level. The dataare shown in FIGS. 5, 6 and 7, respectively. The data demonstrate that asingle dose of Example 9 (DI-1548), Example 21 (DI-1859) or Example 22(DI-1860) effectively increases the level of Nrf2 protein in mouse livertissue.

Analysis of the Effect of Covalent DCN1 Inhibitor Example 21 (DI-1859)in Protection of Mice from Acetaminophen-Induced Liver Injury

Drug-induced liver injury remains an important clinical problemglobally. In the United States, acetaminophen (APAP, or Tylenol)overdose is responsible for more than 50% of overdose-related acuteliver failure and approximately 20% of the liver transplant cases (Yoon,et al. 2016). Example 21 (DI-1859) effectively induces upregulation ofNRF2 protein in mouse liver. One of the potential therapeuticapplications through upregulation of NRF2 is protection of tissue damageinduced by acetaminophen (APAP). Accordingly, Example 21 (DI-1859) wasevaluated for its ability to protect or reduce APAP-induced liver injuryin mice, with the data summarized in FIG. 8.

To induce acute liver injury, mice were administered a large dose (400mg/kg) of APAP via intraperitoneal (I.P.) injection and were sacrificed48 hr later. To examine the protective effect of DI-1859 (pretreatment),animals were I.P. injected with DI-1859 for three consecutive days (oneday before APAP injection, three hours before APAP injection and a thirddose on the next day after APAP injection). To examine the restorativeeffect of DI-1859 (post-treatment), mice were treated with DI-1859 threehours after APAP administration followed by two additional doses on thefollowing two days. Two control groups of mice were treated withphosphate-buffered saline (PBS) or DI-1859, respectively. Blood samplecollection was performed on each day.

The activity of alanine aminotransferase (ALT) in blood is a commonlyused measurement clinically as a part of a diagnostic evaluation ofliver injury, to determine liver health. Therefore, the blood ALTactivity was measured using an ALT reagent set (Pointe Scientific Inc.,Canton, Mich.). The data showed that pretreatment with DI-1859effectively reduces the dramatically elevated levels of alanineaminotransferase (ALT) activity induced by APAP in a dose-dependentmanner (FIG. 8). DI-1859 at 50 mg/kg completely prevents the elevationof ALT activity by APAP. Furthermore, post-treatment of APAP withDI-1859 at 50 mg/kg reduces the APAP-induced elevated ALT level byapproximately 50%. These data (FIG. 8) demonstrate that DI-1859 is veryeffective in reducing the APAP-induced liver tissue damage in eitherprevention or treatment setting.

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The invention claimed is:
 1. A compound having a structural formula (I)

wherein; Q is C═O, C═S or SO₂; Ar₁ is a five or six-membered aromatic orheteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having8-12 atoms, including up to four heteroatoms chosen from N, O and S, ina chemically stable arrangement, optionally substituted with up to fourR₂ substituents; T is halogen, SS—C₁₋₆ lower alkyl, pentafluorophenoxy,tetrafluorophenoxy: X is selected from a bond, CR₇R₈, CR₇R₈NR₁₂,CR₇R₈NR₁₂CO, CR₇R₈NR₁₂CONR₁₂, CR₇R₈NR₁₂SO₂, CR₇R₈O, CR₇R₈S(O)x CONR₁₂; Yis selected from C₁₋₆ alkylidyl, C₃₋₆ cycloalkylidyl, C₄₋₇heterocloalkylidyl, arylene, heteroarylene, aryl(m)ethylene,heteroaryl(m)ethylene, fused C₅₋₈ bicycloalkylidyl or C₅₋₉spirocycloalkylidyl; or Y and R₉ are taken together with the nitrogenatom to which they are attached to form a heterocyclic or heteroarylring of four to seven members, optionally including any chemicallystable combination of one to three groups selected from O, C═O, N, NR₅and S; Z is

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl; R₂ are independently selectedfrom the group consisting of halo, CN, N₃, CF₃, NO₂, H, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl, C₂₋₆alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆cycloalkyl, C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl,substituted monocyclic heteroaryl, OR₅, NR₃R₄, COOR₅, CONR₃R₄; R₃ andR₄, independently, are selected from the group consisting of hydrogen,C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl, heteroaryl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl, C₁₋₆acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl, aroyl,heteroaroyl, or are taken together with the nitrogen atom to which theyare attached to form a ring of four to seven members, optionallyincluding any chemically stable combination of one to three O, C═O, NR₅and S; R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂,C₁₋₆ alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆cycloalkenyl, C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆cycloalkyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆alkyl-heteroaryl, C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionallysubstituted with up to three substituents independently selected fromhalo, hydroxy, oxo, thio, thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₄₋₇ heterocycloalkyl,aryl, and heteroaryl; R₆ is selected from the group consisting of C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, C₂₋₆ alkynyl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆alkyl-C₄₋₆ cycloalkenyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆alkylaryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl andC₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl; R₇ and R₈ may be independently H, C₁₋₆alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl,C₂₋₆ alkynyl, substituted C₂₋₆ alkynyl, or taken together with the Catom to which they are attached, form a carbonyl group, a thionyl group,an oxime, a hydrazone, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl or C₄₋₇heterocycloalkyl: R₉ is selected from the group consisting of H, C₁₋₆alkyl, substituted C₁₋₆ alkyl, C₃₋₆ alkenyl, substituted C₃₋₆ alkenyl,C₃₋₆ alkynyl, substituted C₃₋₆ alkynyl, C₃₋₆ cycloalkyl, substitutedC₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl,phenyl, substituted phenyl, monocyclic heteroaryl, substitutedmonocyclic heteroaryl or C₄₋₇ heterocycloalkyl: R₁₀ is H, F, Cl, CF₃,CHF₂, (CH₂)_(n)NR₃R₄, CH₂SO₂R₁₂, CH₂OCOR₁₂, CN or R₁₂; R_(11e) is H,R₁₂, (CH₂)_(n)R₂, CF₂(CH₂)_(x)R₂, COR₅, CO₂R₅ or CONR₃R₄; R_(11z) is H,F, Cl, CF₃, CHF₂, CF₂R₁₂ or R₁₂; or R_(11e) and R_(11z) may be takentogether with the sp² carbon atom to which both are bonded to form analicyclic ring of 4 to 7 members where one of the ring atoms may beNR₁₂, O, or S(O)_(x), optionally substituted with halogen, oxo, OH, OR₅,NR₃R₄; or R_(11e) and R_(11z) taken together may be R_(11e)R_(11z)C═,forming an allenyl group; or R₁₀ and R_(11e) may be taken together withthe sp² C atoms to which they are attached to form a partially saturatedcarbocyclic or heterocyclic ring of 5-7 atoms, with up to two of thering atoms being O, S(O)_(x), NR₁₂, and said ring may be substitutedwith hydroxy, oxo, C₁₋₆ alkoxy, R_(11t) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl,aryl, heteroaryl, C₄₋₇ heterocycloalkyl, CH₂NR₃R₄; R₁₂ is H or C₁₋₆alkyl, either straight chain or branched; n is 1, 2 or 3; x is 0, 1, or2; or a pharmaceutically acceptable salt, hydrate, or solvate thereof.2. The compound of claim 1

wherein; Q is C═O; Ar₁ is a five or six-membered aromatic orheteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having8-12 atoms, including up to four heteroatoms chosen from N, O and S, ina chemically stable arrangement, optionally substituted with up to fourR₂ substituents; T is halogen: X is selected from a bond, CR₇R₈,CR₇R₈NR₁₂, CR₇R₈NR₁₂CO, CR₇R₈NR₁₂CONR₁₂, CR₇R₈NR₁₂SO₂, CR₇R₈O,CR₇R₈S(O)x CONR₁₂; Y is selected from C₁₋₆ alkylidyl, C₃₋₆cycloalkylidyl, C₄₋₇ heterocloalkylidyl, arylene, heteroarylene,aryl(m)ethylene, heteroaryl(m)ethylene; or Y and R₉ are taken togetherwith the nitrogen atom to which they are attached to form a heterocyclicor heteroaryl ring of four to seven members, optionally including anychemically stable combination of one to three groups selected from O,C═O, N, NR₅ and S; Z is

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl; R₂ are independently selectedfrom the group consisting of halo, CN, N₃, CF₃, NO₂, H, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl, C₂₋₆alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆cycloalkyl, C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl,substituted monocyclic heteroaryl, OR₅, NR₃R₄, COOR₅, CONR₃R₄; R₃ andR₄, independently, are selected from the group consisting of hydrogen,C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl, heteroaryl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl, C₁₋₆acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl, aroyl,heteroaroyl, or are taken together with the nitrogen atom to which theyare attached to form a ring of four to seven members, optionallyincluding any chemically stable combination of one to three O, C═O, NR₅and S; R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂,C₁₋₆ alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆cycloalkenyl, C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆cycloalkyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆alkyl-heteroaryl, C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionallysubstituted with up to three substituents independently selected fromhalo, hydroxy, oxo, thio, thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₄₋₇ heterocycloalkyl,aryl, and heteroaryl; R₆ is selected from the group consisting of C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, C₂₋₆ alkynyl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆alkyl-C₄₋₆ cycloalkenyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆alkylaryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl andC₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl; R₇ and R₈ may be independently H, C₁₋₆alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl,C₂₋₆ alkynyl, substituted C₂₋₆ alkynyl, or taken together with the Catom to which they are attached, form a carbonyl group, a thionyl group,an oxime, a hydrazone, C₃₋₆ cycloalkyl, substituted C₃₋₆ cycloalkyl,C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl or C₄₋₇heterocycloalkyl: R₉ is selected from the group consisting of H, C₁₋₆alkyl, substituted C₁₋₆ alkyl, C₃₋₆ alkenyl, substituted C₃₋₆ alkenyl,C₃₋₆ alkynyl, substituted C₃₋₆ alkynyl, C₃₋₆ cycloalkyl, substitutedC₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl,phenyl, substituted phenyl, monocyclic heteroaryl, substitutedmonocyclic heteroaryl or C₄₋₇ heterocycloalkyl: R₁₀ is H, F, CF₃, CHF₂,(CH₂)_(n)NR₃R₄, CN or R₁₂; R_(11e) is H, R₁₂, (CH₂)_(n)R₂,CF₂(CH₂)_(x)R₂, COR₅, CO₂R₅ or CONR₃R₄; R_(11z) is H, F, Cl, CF₃, CHF₂;Or R_(11e) and R_(11z) may be taken together with the sp² carbon atom towhich both are bonded to form an alicyclic ring of 4 to 7 members whereone of the ring atoms may be NR₁₂, O, or S(O)_(x), optionallysubstituted with halogen, oxo, OH, OR₅, NR₃R₄; or R₁₀ and R_(11e) may betaken together with the sp² C atoms to which they are attached to form apartially saturated carbocyclic or heterocyclic ring of 5-7 atoms, withup to two of the ring atoms being O, S(O)_(x), NR₁₂, and said ring maybe substituted with hydroxy, oxo, C₁₋₆ alkoxy, R_(11t) is C₁₋₆ alkyl,C₃₋₆ cycloalkyl, C₄₋₇ heterocycloalkyl, CH₂NR₃R₄; R₁₂ is H or C₁₋₆alkyl, either straight chain or branched; n is 1, 2 or 3; x is 0, 1, or2; or a pharmaceutically acceptable salt, hydrate, or solvate thereof.3. The compound of claim 1

wherein; Ar₁ is a five or six-membered aromatic or heteroaromatic ringor a bicyclic aromatic or heteroaromatic ring having 8-12 atoms,including up to four heteroatoms chosen from N, O and S, in a chemicallystable arrangement, optionally substituted with up to four R₂substituents; T is halogen: X—Y is selected from the group consistingof:

such that Ar₂ is monocyclic arylene or heteroarylene; Z is

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl; R₂ are independently selectedfrom the group consisting of halo, CN, N₃, CF₃, NO₂, H, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl, C₂₋₆alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆cycloalkyl, C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl,substituted monocyclic heteroaryl, OR₅, NR₃R₄, COOR₅, CONR₃R₄; R₃ andR₄, independently, are selected from the group consisting of hydrogen,C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl, heteroaryl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl, C₁₋₆acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl, aroyl,heteroaroyl, or are taken together with the nitrogen atom to which theyare attached to form a ring of four to seven members, optionallyincluding any chemically stable combination of one to three O, C═O, NR₅and S; R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂,C₁₋₆ alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆cycloalkenyl, C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆cycloalkyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆alkyl-heteroaryl, C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionallysubstituted with up to three substituents independently selected fromhalo, hydroxy, oxo, thio, thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₄₋₇ heterocycloalkyl,aryl, and heteroaryl; R₆ is selected from the group consisting of C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, C₂₋₆ alkynyl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆alkyl-C₄₋₆ cycloalkenyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆alkylaryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl andC₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl; R₉ is selected from the group consistingof H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₆ alkenyl, substituted C₃₋₆alkenyl, C₃₋₆ alkynyl, substituted C₃₋₆ alkynyl, C₃₋₆ cycloalkyl,substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substituted C₄₋₆cycloalkenyl, phenyl, substituted phenyl, monocyclic heteroaryl,substituted monocyclic heteroaryl or C₄₋₇ heterocycloalkyl: R₁₀ is H,(CH₂)_(n)NR₃R₄, CN or R₁₂; R_(11e) is H, R₁₂, or (CH₂)_(n)NR₃R₄; R_(11z)is H, F, Cl, CF₃, CHF₂; Or R₁₀ and R_(11e) may be taken together withthe sp² C atoms to which they are attached to form a partially saturatedcarbocyclic or heterocyclic ring of 5-7 atoms, with up to two of thering atoms being O, S(O)_(x), NR₁₂, and said ring may be substitutedwith hydroxy, oxo, C₁₋₆ alkoxy, R_(11t) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₄₋₇ heterocycloalkyl, CH₂NR₃R₄; R₁₂ is H or C₁₋₆ alkyl, either straightchain or branched; l is 2-4; m is 2-6; n is 1, 2 or 3; x isindependently 0, 1, or 2; or a pharmaceutically acceptable salt,hydrate, or solvate thereof.
 4. The compound of claim 1

wherein; Q is C═O; Ar₁ is a five or six-membered aromatic orheteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having8-12 atoms, including up to four heteroatoms chosen from N, O and S, ina chemically stable arrangement, optionally substituted with up to fourR₂ substituents; T is halogen: X, Y and R₉ are taken together with thenitrogen atom to which they are attached to form a ring which selectedfrom the group consisting of:

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl; R₂ are independently selectedfrom the group consisting of halo, CN, N₃, CF₃, NO₂, H, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl, C₂₋₆alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆cycloalkyl, C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl,substituted monocyclic heteroaryl, OR₅, NR₃R₄, COOR₅, CONR₃R₄; R₃ andR₄, independently, are selected from the group consisting of hydrogen,C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl, heteroaryl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl, C₁₋₆acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl, aroyl,heteroaroyl, or are taken together with the nitrogen atom to which theyare attached to form a ring of four to seven members, optionallyincluding any chemically stable combination of one to three O, C═O, NR₅and S; R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂,C₁₋₆ alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆cycloalkenyl, C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆cycloalkyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆alkyl-heteroaryl, C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionallysubstituted with up to three substituents independently selected fromhalo, hydroxy, oxo, thio, thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₄₋₇ heterocycloalkyl,aryl, and heteroaryl; R₆ is selected from the group consisting of C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, C₂₋₆ alkynyl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆alkyl-C₄₋₆ cycloalkenyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆alkylaryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl andC₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl; R₁₀ is H, (CH₂)_(n)NR₃R₄, CN or R₁₂;R_(11e) is H, R₁₂, or (CH₂)_(n)NR₃R₄; R_(11z) is H, F, Cl, CF₃, CHF₂; orR₁₀ and R_(11e) may be taken together with the sp² C atoms to which theyare attached to form a partially saturated carbocyclic or heterocyclicring of 5-7 atoms, with up to two of the ring atoms being O, S(O)_(x),NR₁₂, and said ring may be substituted with hydroxy, oxo, C₁₋₆ alkoxy,R_(11t) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocycloalkyl, CH₂NR₃R₄;R₁₂ is H or C₁₋₆ alkyl, either straight chain or branched; m is 2-6; nis 1, 2 or 3; x is independently 0, 1, or 2; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof.
 5. The compound of claim 1

wherein; Q is C═O; Ar₁ is a five or six-membered aromatic orheteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having8-12 atoms, including up to four heteroatoms chosen from N, O and S, ina chemically stable arrangement, optionally substituted with up to fourR₂ substituents; X—Y is selected from the group consisting of:

such that Ar₂ is monocyclic arylene or heteroarylene; Z is

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl; R₂ are independently selectedfrom the group consisting of halo, CN, N₃, CF₃, NO₂, H, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl, C₂₋₆alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆cycloalkyl, C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl,substituted monocyclic heteroaryl, OR₅, NR₃R₄, COOR₅, CONR₃R₄; R₃ andR₄, independently, are selected from the group consisting of hydrogen,C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl, heteroaryl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl, C₁₋₆acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl, aroyl,heteroaroyl, or are taken together with the nitrogen atom to which theyare attached to form a ring of four to seven members, optionallyincluding any chemically stable combination of one to three O, C═O, NR₅and S; R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂,C₁₋₆ alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆cycloalkenyl, C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆cycloalkyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆alkyl-heteroaryl, C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionallysubstituted with up to three substituents independently selected fromhalo, hydroxy, oxo, thio, thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₄₋₇ heterocycloalkyl,aryl, and heteroaryl; R₆ is selected from the group consisting of C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, C₂₋₆ alkynyl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆alkyl-C₄₋₆ cycloalkenyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆alkylaryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl andC₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl; R₉ is H; or R₁₀ is H, CN or CH₂NR₃R₄;R_(11e) and R_(11z) are H or one may be R₁₂; R₁₂ is H or C₁₋₆ alkyl,either straight chain or branched; l is 2-4; m is 2-6; n is 1, 2 or 3; xis independently 0, 1, or 2; or a pharmaceutically acceptable salt,hydrate, or solvate thereof.
 6. The compound of claim 1

wherein; Q is C═O; Ar₁ is a five or six-membered aromatic orheteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having8-12 atoms, including up to four heteroatoms chosen from N, O and S, ina chemically stable arrangement, optionally substituted with up to fourR₂ substituents; X, Y and R₉ are taken together with the nitrogen atomto which they are attached to form a ring which selected from the groupconsisting of:

Z is

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl; R₂ are independently selectedfrom the group consisting of halo, CN, N₃, CF₃, NO₂, H, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl, C₂₋₆alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆cycloalkyl, C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl,substituted monocyclic heteroaryl, OR₅, NR₃R₄, COOR₅, CONR₃R₄; R₃ andR₄, independently, are selected from the group consisting of hydrogen,C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl, heteroaryl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl, C₁₋₆acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl, aroyl,heteroaroyl, or are taken together with the nitrogen atom to which theyare attached to form a ring of four to seven members, optionallyincluding any chemically stable combination of one to three O, C═O, NR₅and S; R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂,C₁₋₆ alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆cycloalkenyl, C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆cycloalkyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆alkyl-heteroaryl, C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionallysubstituted with up to three substituents independently selected fromhalo, hydroxy, oxo, thio, thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₄₋₇ heterocycloalkyl,aryl, and heteroaryl; R₆ is selected from the group consisting of C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, C₂₋₆ alkynyl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆alkyl-C₄₋₆ cycloalkenyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆alkylaryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl andC₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl; R₁₀ is H, CN or CH₂NR₃R₄; R_(11e) andR_(11z) are H or one may be R₁₂; R₁₂ is H or C₁₋₆ alkyl, either straightchain or branched; m is 2-6; n is 1, 2 or 3; x is independently 0, 1, or2; or a pharmaceutically acceptable salt, hydrate, or solvate thereof.7. The compound of claim 1 of Formula (II)

wherein: Ar₁ is a five or six-membered aromatic or heteroaromatic ringor a bicyclic aromatic or heteroaromatic ring having 8-12 atoms,including up to four heteroatoms chosen from N, O and S, in a chemicallystable arrangement, optionally substituted with up to four R₂substituents; R₁ is selected from the group consisting of H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl; R₂ are independently selectedfrom the group consisting of halo, CN, N₃, CF₃, NO₂, H, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl, C₂₋₆alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆cycloalkyl, C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl,substituted monocyclic heteroaryl, OR₅, NR₃R₄, COOR₅, CONR₃R₄; R₃ andR₄, independently, are selected from the group consisting of hydrogen,C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl, heteroaryl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl, C₁₋₆acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl, aroyl,heteroaroyl, or are taken together with the nitrogen atom to which theyare attached to form a ring of four to seven members, optionallyincluding any chemically stable combination of one to three O, C═O, NR₅and S; R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂,C₁₋₆ alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆cycloalkenyl, C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆cycloalkyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆alkyl-heteroaryl, C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionallysubstituted with up to three substituents independently selected fromhalo, hydroxy, oxo, thio, thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₄₋₇ heterocycloalkyl,aryl, and heteroaryl; R₆ is selected from the group consisting of C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, C₂₋₆ alkynyl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆alkyl-C₄₋₆ cycloalkenyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆alkylaryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl andC₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl; R₉ is selected from the group consistingof H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₆ alkenyl, substituted C₃₋₆alkenyl, C₃₋₆ alkynyl, substituted C₃₋₆ alkynyl, C₃₋₆ cycloalkyl,substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substituted C₄₋₆cycloalkenyl, phenyl, substituted phenyl, monocyclic heteroaryl,substituted monocyclic heteroaryl or C₄₋₇ heterocycloalkyl: R₁₀ is H, F,Cl, CF₃, CHF₂, (CH₂)_(n)NR₃R₄, CH₂SO₂R₁₂, CH₂OCOR₁₂, CN or R₁₂; R_(11e)is H, R₁₂, (CH₂)_(n)R₂, CF₂(CH₂)_(x)R₂, COR₅, CO₂R₅ or CONR₃R₄; R_(11z)is H, F, Cl, CF₃, CHF₂, CF₂R₁₂ or R₁₂; Or R_(11e) and R_(11z) may betaken together with the sp² carbon atom to which both are bonded to forman alicyclic ring of 4 to 7 members where one of the ring atoms may beNR₁₂, O, or S(O)_(x), optionally substituted with halogen, oxo, OH, OR₅,NR₃R₄; or R_(11e) and R_(11z) taken together may be R_(11e)R_(11z)C═,forming an allenyl group; or R₁₀ and R_(11e) may be taken together withthe sp² C atoms to which they are attached to form a partially saturatedcarbocyclic or heterocyclic ring of 5-7 atoms, with up to two of thering atoms being O, S(O)_(x), NR₁₂, and said ring may be substitutedwith hydroxy, oxo, C₁₋₆ alkoxy, R_(11z) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl,aryl, heteroaryl, C₄₋₇ heterocycloalkyl, CH₂NR₃R₄; R₁₂ is H or C₁₋₆alkyl, either straight chain or branched; n is 1, 2 or 3; x is 0, 1, or2; or a pharmaceutically acceptable salt, hydrate, or solvate thereof.8. The compound of claim 1 of Formula (III)

wherein: Ar₁ is a five or six-membered aromatic or heteroaromatic ringor a bicyclic aromatic or heteroaromatic ring having 8-12 atoms,including up to four heteroatoms chosen from N, O and S, in a chemicallystable arrangement, optionally substituted with up to four R₂substituents; R₁ is selected from the group consisting of H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylmethylene, NHMe, N(Me)₂, NHEt,NH-cyclopropyl, OMe, OEt, O-cyclopropyl; R₂ are independently selectedfrom the group consisting of halo, CN, N₃, CF₃, NO₂, H, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl, C₂₋₆alkynyl, substituted C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, substituted C₃₋₆cycloalkyl, C₄₋₆ cycloalkenyl substituted C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl,substituted monocyclic heteroaryl, OR₅, NR₃R₄, COOR₅, CONR₃R₄; R₃ andR₄, independently, are selected from the group consisting of hydrogen,C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇ heterocyclyl, aryl, heteroaryl,C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆ cycloalkenyl, C₁₋₆alkyl-C₄₋₆ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆ alkyl-heteroaryl, C₁₋₆acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇ heterocycloalkylcarbonyl, aroyl,heteroaroyl, or are taken together with the nitrogen atom to which theyare attached to form a ring of four to seven members, optionallyincluding any chemically stable combination of one to three O, C═O, NR₅and S; R₅ is selected from the group consisting of hydrogen, CF₃, CHF₂,C₁₋₆ alkyl, allyl, propargyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl-C₄₋₆cycloalkenyl, C₄₋₇ heterocycloalkyl, aryl, heteroaryl, C₁₋₆ alkyl-C₃₋₆cycloalkyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, C₁₋₆ alkaryl, C₁₋₆alkyl-heteroaryl, C₁₋₆ acyl, C₃₋₆ cycloalkylcarbonyl, C₄₋₇heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionallysubstituted with up to three substituents independently selected fromhalo, hydroxy, oxo, thio, thiono, amino, cyano, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₄₋₇ heterocycloalkyl,aryl, and heteroaryl; R₆ is selected from the group consisting of C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₄₋₆ cycloalkenyl, C₄₋₇heterocycloalkyl, C₂₋₆ alkynyl, C₁₋₆ alkyl-C₃₋₆ cycloalkyl, C₁₋₆alkyl-C₄₋₆ cycloalkenyl, C₁₋₆ alkyl-C₄₋₇ heterocycloalkyl, aryl, C₁₋₆alkylaryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, C₅₋₁₀ bicycloalkyl andC₁₋₆ alkyl-C₅₋₁₀ bicycloalkyl; R₉ is selected from the group consistingof H, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₆ alkenyl, substituted C₃₋₆alkenyl, C₃₋₆ alkynyl, substituted C₃₋₆ alkynyl, C₃₋₆ cycloalkyl,substituted C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl substituted C₄₋₆cycloalkenyl, phenyl, substituted phenyl, monocyclic heteroaryl,substituted monocyclic heteroaryl or C₄₋₇ heterocycloalkyl: n is 1, 2 or3; x is 0, 1, or 2; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof.
 9. The compound of claim 8 of Formula (III)

wherein: Ar₁ is benzothiazol-2-yl, benzoxazol-2-yl, naphth-2-yl,4-methyl-5-phenylthiazole, 4-methyl-5-phenyloxazole andimidazo[1,2-a]pyrid-2-yl, whereby each 6-membered aromatic ring in maybe substituted with up to two R₂ substituents selected from C₁₋₆ loweralkyl, CF₃, and halogen; R₁ is methyl, ethyl, methylamino, cyclopropyl,isopropyl or n-propyl; R₃ and R₄, independently, are selected from thegroup consisting of C₁₋₆ alkyl, allyl, C₃₋₆ cycloalkyl, C₄₋₇heterocyclyl, or are taken together with the nitrogen atom to which theyare attached to form a ring of four to seven members, optionallyincluding any chemically stable combination of one to three O, C═O, NR₅and S; R₅ is C₁₋₄ alkyl, C₁₋₄ acyl, C₂₋₄ hydroxyalkyl, C₁₋₂ alkoxy-C₂₋₄alkyl, oxetan-3-yl, oxolan-3-yl, oxan-4-yl, N-methylazetidin-3-yl,N-methylpyrrolidin-3-yl or N-methylpiperidin-4-yl; R₆ is benzyl,isopropyl, [R]- or [S]-2-butyl, 3-pentyl, cyclopentyl, cyclohexyl,cyclohexylmethyl, cyclpentylmethyl, 4-tetrahydrofuranyl or isopropyl; R₉is H, C₁₋₄ alkyl, C₂₋₄ hydroxyalkyl, C₁₋₂ alkoxy-C₂₋₄ alkyl,oxetan-3-yl, oxolan-3-yl, oxan-4-yl, N-methylazetidin-3-yl,N-methylpyrrolidin-3-yl or N-methylpiperidin-4-yl.
 10. The compound ofclaim 1 wherein Ar₁ is selected from benzothiazol-2-yl, benzoxazol-2-yl,naphtha-2-yl, 4-methyl-5-phenylthiazole, 4-methyl-5-phenyloxazole,imidazo[1,2-a]pyrid-2-yl, whereby each 6-membered aromatic ring may besubstituted with up to two R₂ substituents selected from C₁₋₆ loweralkyl, CF₃ and halogen.
 11. The compound of claim 5 wherein Ar₁ isselected from benzothiazol-2-yl, benzoxazol-2-yl, naphtha-2-yl,4-methyl-5-phenylthiazole, 4-methyl-5-phenyloxazole,imidazo[1,2-a]pyrid-2-yl whereby each 6-membered aromatic ring may besubstituted with up to two R₂ substituents selected from C₁₋₆ loweralkyl, CF₃ and halogen.
 12. The compound of claim 6 wherein Ar₁ isselected from benzothiazol-2-yl, benzoxazol-2-yl, naphtha-2-yl,4-methyl-5-phenylthiazole, 4-methyl-5-phenyloxazole,imidazo[1,2-a]pyrid-2-yl whereby each 6-membered aromatic ring may besubstituted with up to two R₂ substituents selected from C₁₋₆ loweralkyl, CF₃ and halogen.
 13. The compound of claim 1 wherein Z isacryloyl, or 2-(aminomethyl)acryloyl, such that the amine is substitutedwith R₃ and R₄, and neither is hydrogen.
 14. The compound of claim 5wherein Z is acryloyl, or 2-(aminomethyl)acryloyl, such that the amineis substituted with R₃ and R₄, and neither is hydrogen.
 15. The compoundof claim 6 wherein Z is acryloyl, or 2-(aminomethyl)acryloyl, such thatthe amine is substituted with R₃ and R₄, and neither is hydrogen. 16.The following compounds of claim 1:

or pharmaceutically acceptable salts, hydrates or solvates thereof. 17.A compound of the following structure,

or pharmaceutically acceptable salts, hydrates or solvates thereof. 18.A compound of the following structure

or pharmaceutically acceptable salts, hydrates or solvates thereof. 19.The compound of claim 1 which can form a covalent bond with Cys¹¹⁵ ofDCN1.
 20. The compound of claim 1 which can form a covalent bond withCys¹¹⁵ of DCN1 in vivo, when dosed systemically to a mammal.
 21. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier vehicle.
 22. A method of treatingacetaminophen-induced liver injury comprising administering atherapeutically effective amount of a compound of claim 1 to anindividual in need thereof.